(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Properly Organization
International Bureau
(43) International Publication Date
22 June 2006 (22.06.2006)
PCT
(10) International Publication Number
WO 2006/065280 A2
(51) International Patent Classification :
A61K 31/44 (2006.01) C07D 471/02 (2006.01)
(21) International Application Number:
PCT/US2005/021570
17 June 2005(17.06.2005)
English
English
(22) International Filing Date:
(25) Filing Language:
(26) Publication Language:
(30) Priority Data:
60/580,989
60/665,520
18 June 2004 (18.06.2004) US
25 March 2005 (25.03.2005) US
(71) Applicant (for all designated States except US): 3M
INNOVATIVE PROPERTIES COMPANY [US/US];
3M Center, Post Office Box 33427, Saint Paul, Minnesota
55133-3427 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): MOSER, William
H., [US/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US). MOSEMAN, Joan T.,
[US/US]; 3M Center, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US). KSHIRSAGAR, Tushar
A., [IN/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US). HEPPNER, Philip D.,
[US/US]; 3M Center, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US).
(74) Agents: ERSFELD, Dean A., et al.; 3M Center, Office
of Intellectual Property Counsel, Post Office Box 33427,
Saint Paul, Minnesota 55133-3427 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, Gi l, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
VN, YU, ZA, ZM, ZW.
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, TT, LT, LU, MC, NL, PL, PT, RO,
SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
GQ, GW, ML, MR, NE, SN, TD, TG).
Declarations under Rule 4.17:
— as to applicants entitlement to apply for and be granted a
patent (Rule 4.17(H))
— as to the applicant's entitlement to claim the priority of the
earlier application (Rule 4A7(iii))
Published:
— without international search report and to be republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at tlie begin-
ning of each regular issue of the PCV Gazette.
S5 (54) Title: ISOXAZOLE, DTHYDROISOXAZOLE, AND OXADIAZOLE SUBSTITUTED TMTDAZO RING COMPOUNDS
= AND METHODS
™ (57) Abstract: Imidazo ring compounds, (e.g., imidazo[4,5-c]pyridine, imidazo[4,5-c)quinoline, 6,7,8,9-tetrahydro imidazo[4,5-
c]quinoline, imidazo[4,5-c]naphthyridine, and 6,7,8,9-tetrahydro imidazo[4,5-c]naphthyridine compounds) having an isoxazole, di-
hydroisoxazole, or oxadiazole substituent at the 1 -position, pharmaceutical compositions containing the compounds, intermediates,
s and methods of making and methods of use of these compounds as immunomodulators, for modulating cytokine biosynthesis in
= animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
<
00
<N
IT)
o
WO 2006/065280
PCT/US2005/021570
ISOXAZOLE, DIHYDROISOXAZOLE, AND OXADIAZOLE SUBSTITUTED
IMIDAZO RING COMPOUNDS AND METHODS
CROSS REFERENCE TO RELATED APPLICATIONS
The present invention claims priority to U.S. Provisional Application Serial No.
60/665520, filed March 25, 2005, and U.S. Provisional Application Serial No. 60/580989,
filed June 18, 2004, both of which are incorporated herein by reference.
BACKGROUND
In the 1950's the lff-inudazo[4,5-c]quinoline ring system was developed, and l-(6-
methoxy-8-quinolinyl)-2-methyl-lH-imidazo[4,5-c]quinoline was synthesized for possible
use as an antimalarial agent. Subsequently, syntheses of various substituted IH-
imidazo[4,5-c]quinohnes were reported. For example, l-[2-(4-piperidyl)ethyl]-l#-
imidazo[4,5-c]qumoline was synthesized as a possible anticonvulsant and cardiovascular
agent. Also, several 2-oxoimidazo[4,5-c]quinolines have been reported.
Certain l/74midazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives
thereof were later found to be useful as antiviral agents, bronchodilators and
immunomodulators. Subsequently, certain substituted l/?-imidazo[4,5-c]pyridin-4-amine,
quinolin-4-amine, tetrahydroquinolin-4-amine, naphthyridin-4-amine, and
tetrahydronaphthyridin-4-amine compounds as well as certain analogous thiazolo and
oxazolo compounds were synthesized and found to be useful as immune response
modifiers, rendering them useful in the treatment of a variety of disorders.
There continues to be interest in and a need for compounds that have the ability to
modulate the immune response, by induction of cytokine biosynthesis or other
mechanisms.
SUMMARY
It has now been found that compounds of Formula I are useful as immune response
modifiers. The present invention, therefore, provides a new class of immune response
modifying compounds of the following Formula I:
1
WO 2006/065280
PCT/US2005/021570
NH 2
N
V-R 2
N
I
wherein X 1 , Ri, Ra, Rb, and R2 are as defined below.
The compounds of Formula I are useful as immune response modifiers due to their
ability to induce cytokine biosynthesis (e.g., induce the synthesis of at least one cytokine)
and otherwise modulate the immune response when administered to animals. This makes
the compounds useful in the treatment of a variety of conditions such as viral diseases and
tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing an
effective amount of a compound of Formula I and methods of inducing cytokine
biosynthesis in an animal, treating a viral infection or disease and/or treating a neoplastic
disease in an animal by administering an effective amount of a compound of Formula I to
the animal.
In addition, methods of synthesizing compounds of Formula I and intermediates
useful in the synthesis of these compounds are provided.
As used herein, "a," "an," "the," "at least one," and "one or more" are used
interchangeably.
The terms "comprises" and variations thereof do not have a limiting meaning
where these terms appear in the description and claims.
The above summary of the present invention is not intended to describe each
disclosed embodiment or every implementation of the present invention. The description
that follows more particularly exemplifies illustrative embodiments. In several places
throughout the description, guidance is provided through lists of examples, which
examples can be used in various combinations. In each instance, the recited list serves
only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
The present invention provides compounds of the following Formula I:
WO 2006/065280
PCT/US2005/021570
R A X 1 R 1
I
as well as more specific compounds of the following Formulas II through VIII, IXa, Kb,
IXc, and DCd:
vi vn
WO 2006/065280
PCT/US2005/021570
NH 2
NH,
HN ^/ X'— R.,
N
H
DCb
NH,
IXc
IXd
and intermediates of the following Formula X:
CI
10
wherein X', Rj, Ra, Rb> Rai, Rbi, Ra, Rb» Re> R2, m, and n are as defined below.
In one embodiment, the present invention provides a compound of Formula I:
15
wherein:
4
WO 2006/065280
PCT/US2005/021570
X 1 is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
R is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
WO 2006/065280 PCT/US2005/021570
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)o. 2 -alkyl,
5 -S(O) 0 -2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
10 nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
. 15 aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R*)-C(0)-alkyl,
20 -0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<i are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -Nfll^; or Rc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
25 one to four heteroatoms;
Rn is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
30 heteroatom;
wherein the total number of atoms in the ring which includes Rn or R12 is 4 to 9;
A 1 is selected from the group consisting of -0-, -S(0)o-2-> -NC-Q-R*)-, and
6
WO 2006/065280 PCT/US2005/021570
-C(R 9a )2S
R A and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
5 alkyl,
alkenyl,
alkoxy,
alkylthio, and
-N(R 9 ) 2 ;
10 or Ra and Rb taken together form either a fused aryl ring that is unsubstituted or
substituted by one or more R a groups, or a fused 5 to 7 membered saturated ring that is
unsubstituted or substituted by one or more R* groups;
or Ra and Rb taken together form a fused heteroaryl or 5 to 7 membered saturated
ring containing one heteroatom selected from the group consisting of N and S, wherein the
1 5 heteroaryl ring is unsubstituted or substituted by one or more R b groups, and the 5 to 7
membered saturated ring is unsubstituted or substituted by one or more R e groups;
Ra is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
Rb is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl,
20 alkoxy, and -N(R 9 )2;
Re is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R9)2;
R 2 is selected from the group consisting of:
-R4,
25 -X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
30 alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
7
WO 2006/065280
PCT/US2005/021570
-S(O) 0 -2-,
-S(0)rN(R8)-,
-C(R6)-,
-C(R<>)-0-,
-0-C(R6>,
-0-C(0)-0-,
-N(Rs)-Q-,
-C(R6)-N(R 8 >,
-0-C(R 6 )-N(Rs> 5
-C(R«)-N(OR9)-,
-A N-Q —
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
N
, and
, and
8
WO 2006/065280 PCT/US2005/021570
R6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
5 R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(O) 0 - 2 -, -CH 2 -, and
-N(R4)-;
10 Q is selected from the group consisting of a bond, -C(R<>)-, -C(R6)-C(R 6 )-, -S(0) 2 -,
and-S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R*)-, -OC(R*)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
15 or a pharmaceutical^ acceptable salt thereof.
In one embodiment, the present invention provides a compound of Formula II:
NH 2
Rm X'-R,
II
20 wherein:
X' is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkyIene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
9
WO 2006/065280
PCTAJS2005/021570
R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
10
WO 2006/065280
PCTYUS2005/021570
-S(0)o- 2 -alkyl,
-S(0)o- 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(Rs)-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9) 2 ; or Rc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C 2 -6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C 2 , 5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or Ri 2 is 4 to 9;
A' is selected from the group consisting of -O-, -S(0)o- 2 - 9 -N(-Q-R4)-, and
-C(R 9a )2S
Rai and R B i are each independently selected from the group consisting of:
hydrogen,
11
WO 2006/065280
PC17US2005/021570
halogen,
alkyl,
alkenyl,
alkoxy,
10
5
alkylthio, and
-N(R 9 ) 2 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
1 5 heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(O) 0 - 2 -,
-S(0) 2 -N(R 8 )-,
20
-C(R«K
-C(R6)-0-,
-0-C(R 6 )-,
-0-C(0)-0-,
-N(Rg)-Q-,
25
-CW-NCRg)-,
-0-C(R 6 )-N(R 8 )-,
-C(R6)-N(OR 9 )-,
, and
WO 2006/065280
PCT/US2005/021570
— V-N
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -O, -C(O)-, -S(0)o-2-, -CH2-, and
-N(R4>;
Q is selected from the group consisting of a bond, -C(Rs)-, -C(R6)-C(R6)-, -S(0)2-,
and -S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R$)-, -0-C(Rs)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
, and
<7;
or a pharmaceutical^ acceptable salt thereof.
13
WO 2006/065280 PCT/US2005/021570
In one embodiment, the present invention provides a compound of Formula III:
wherein:
X' is selected from the group consisting of -CH(R 9 )-, -CHCR^-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
o o R* -J*"9 R'
R'
r. N '0 ^.O R . R /N 0 , N
R'
10 - A ', . , ,and
R'
-C(R 9a ) 2 -N^N
R - r; 2
R c
Rd
R 1 is selected from the group consisting of:
hydrogen,
alkyl,
15 alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
14
WO 2006/065280
PCT/US2005/021570
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)o- 2 -alkyl 5
-S(O) 0 -2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or Rc and
15
WO 2006/065280
PCI7US2005/021570
can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci_6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
5 R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or R i2 is 4 to 9;
A 1 is selected from the group consisting of -0-, -S(0)o-2-> -N(-Q-R4)-, and
10 -C(R 9a ) 2 -;
R a is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
n is an integer from 0 to 4;
R 2 is selected from the group consisting of:
15 -R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
20 arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(O) 0 -2-,
25 -S(0) 2 -N(R8h
-C(R6>,
-C(R6)-0-,
-0-C(R6)-,
-0-C(0)-0-,
30 -N(Rs)-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R6)-N(R8h
16
WO 2006/065280
PCT/US2005/021570
-C(R«)-N(OR9)-,
N-Q-
R J
K 10
-N — R 7 — N-Q~
,and
— V-N
Ri.
5 R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
10 are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
15 oxo;
R5 is selected from the group consisting of:
N C(Rg) "N-S(0) 2 _ v ~ti ^
V , R ^ ,and
R6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
20 Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
25 A is selected from the group consisting of -O-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4>;
17
WO 2006/065280
PCT/US2005/021570
Q is selected from the group consisting of a bond, -C(R^)-, -CCR^-C^)-, -S(0)2-,
and -S(0)2-N(Rs)s
V is selected from the group consisting of -C(R^)-, -0-C(R*)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
5 <7;
or a pharmaceutical^ acceptable salt thereof.
In one embodiment, the present invention provides a compound of Formula IV:
10
15
wherein:
X' is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
^ ^ * , , -A? R '
' M /? M I ^P' ,P' \ J t» I
"^r ^ n -^c -c<: "w -a
R' R' N'° N'° R* R' O-N
R'
_ ~. . ..X.
R ' Rl1 -— A * R <= R' W j
> » . , and
R'
C(R 9a ) 2 -N^N
;0
V K 12
Rc R d .
R* is selected from the group consisting of:
hydrogen,
18
WO 2006/065280
PCTYUS2005/021570
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)o- 2 -alkyl,
-S(0)o- 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
~C(0)-N(Rg) 2 ,
19
WO 2006/065280
PCT/US2005/021570
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
and R<j are independently selected from the group consisting of hydrogen,
5 halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 )2; or Rc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
10 R12 is selected from the group consisting of a bond, C1.5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or R12 is 4 to 9;
A 1 is selected from the group consisting of -0-, -S(0)o- 2 -, -N(-Q-R4>, and
15 -C(R 9a )2-;
R c is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R9)2;
n is an integer of 0 to 4;
R 2 is selected from the group consisting of:
20 -R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
25 arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o-2-,
30 -S(0) 2 -N(R 8 )-,
-C(R*K
-C(R6>0-,
20
WO 2006/065280
PCT/US2005/021570
-0-C(R6)-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R,)-N(R8K
-0-C(R 6 )-N(R 8 K
-C(R 6 )-N(OR 9 >,
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
R<5 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
, and
, and
hydroxyalkylenyl, and arylalkylenyl;
21
WO 2006/065280
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R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and C1-4 alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o- 2 - 5 -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(Re)- 9 -C(R 6 )-C(R6)-, -S(0) 2 -,
and-S(0) 2 -N(R 8 )s
V is selected from the group consisting of-CCR*)-, -0-C(Rs)- 5 and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
or a pharmaceutical^ acceptable salt thereof
In one embodiment, the present invention provides a compound selected from the
group consisting Formulas V, VI, VII, and VIII:
NH,
N
' N X'-R., X—R, x'-R
1 , and
vm
wherein:
X* is selected from the group consisting of -CH(R 9 )-, -CH(R9)-alkylene-, and
-CH(R9)-alkenylene-;
Ri is selected from the group consisting of:
22
WO 2006/065280
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R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
23
WO 2006/065280
PCT/US2005/021570
-S(0)o- 2 -alkyl,
-S(O) 0 .2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(Rs) 2 ,
-N(R 8 )-C(0)-alkyl 5
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R* and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci^alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes R\ \ or R i2 is 4 to 9;
A ! is selected from the group consisting of -O-, -S(O) 0 - 2 - 5 -N(-Q-R4)-, and
-C(R 9a ) 2 -;
R b is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl,
alkoxy, and ~N(R 9 ) 2 ;
24
WO 2006/065280
PCT/US2005/021570
m is an integer from 0 to 3;
R.2 is selected from the group consisting of:
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0)2-N(RsK
-C(R<5)-,
-cw-o-,
-0-C(Rfi)-,
-0-C(0)-0-,
-N(R«>Q-,
-C(R6)-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R6)-N(OR 9 )-,
-A N-Q—
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
-R4,
-X-R4,
-X-Y-R4,and
-X-R 5 ;
, and
25
WO 2006/065280
PCT/US2005/021570
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo ;
R 5 is selected from the group consisting of:
Re is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and C1.4 alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4)s
Q is selected from the group consisting of a bond, -C(R6)- 3 -C(R6)-C(R6)-, -S(0)2- 5
and-S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R6)-, -0-C(R6)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a compound selected from the
group consisting Formulas IXa, Kb, IXc, and IXd:
, and
26
WO 2006/065280
PCT/US2005/021570
10
N
il y-^
N (Re)m
NH V- Rl
DCa
X'— R.
1 , and
DCd
wherein:
X' is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R.9)-alkenylene-;
Ri is selected from the group consisting of:
N
R'
R'
R- V°
N"
. -< /N T F
' N^V R ' N^R'
R' R / 0'N
R* Rh/V
R'
-C(R 9a ) 2 -N^N
R,
-<'
N-
12 .
R'
R ; -C(R93) 2 -N^N
i. R Ar - C ( R ^) 2 -N N N R.
R c R R' W
'2 — N N
, and
15
R is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
27
WO 2006/065280
PCTAJS2005/021570
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(O) 0 -2-alkyl,
-S(0)o. 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
28
WO 2006/065280
PCT/US2005/021570
-C(0)-alkyl;
Rc and Rd are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9) 2 ; or Rc and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C 2 »6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or R J2 is 4 to 9;
A* is selected from the group consisting of -0-, -S(0)o- 2 -, -N(-Q-R4)-, and
"C(R 9a )2-;
Re is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
m is an integer from 0 to 3;
R 2 is selected from the group consisting of:
-fU,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-s(oy 2 -,
-S(0) 2 -N(R 8 )-,
-C(R6>,
-C(R6)-0-,
-0-C(R 6 )-,
-OC(0)-0-
29
WO 2006/065280
PCT/US2005/021570
-N(Rg)-Q-,
-C(R«)-N(R«)-,
-O-CCRfiJ-NCRs)-,
-C(R6)-N(OR 9 )- 9
5
Q—
, and
— V-N
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
10 heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
15 hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
20
R<5 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
25
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
WO 2006/065280
PCTAJS2005/021570
Rio is C3-8 alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4)S
Q is selected from the group consisting of a bond, -C(R6>-, -C(R6)-C(R$)-, -S(0)2-,
and-S(0) 2 -N(R«)s
V is selected from the group consisting of -C(R6)-, -OC(R6)-, and -S(0>2-; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
or a pharmaceutical^ acceptable salt thereof.
In one embodiment, the present invention provides an intermediate compound of
Formula X:
X* is selected from the group consisting of -CH(R 9 >, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
<7;
CI
wherein:
31
WO 2006/065280
PCT/US2005/021570
R' is selected from the group consisting of:
hydrogen,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
32
WO 2006/065280
PCT/US2005/021570
-S(O) 0 -2-aIkyl,
-S(0)o-2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R*) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<i are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 )2; or Rc and
R<i can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or Rn is 4 to 9;
A f is selected from the group consisting of -0-, -S(0)o-2-> -N(-Q-R4)-, and
-C(R 9 a)2S
R a is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
33
WO 2006/065280
PCTAJS2005/021570
n is an integer from 0 to 4;
R.2 is selected from the group consisting of:
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R8)-,
-C(R«h
-C(R6)-0-,
-0-C(R6)-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R*)-N(R8)-,
-O-C^-NCRg)-,
-C^-NCORg)-,
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
, and
34
WO 2006/065280
PCT/US2005/021570
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
-N-C(Re) -N-S(0) 2 - V -|d \
V , R ^ ,and W-A
Re is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
R 10 is C3-8 alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4>;
Q is selected from the group consisting of a bond, -C(R<5)-, -C(R6)-C(R$)- 5 -S(0)2-,
and -S(0)2-N(Rg)s
V is selected from the group consisting of -C(R<5)-, -OC(R<s)-, and -S(0)2-; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
or a pharmaceutical^ acceptable salt thereof.
For certain embodiments, there is provided a compound (which is a prodrug) of the
Formula 1-1:
35
WO 2006/065280
PCT/US2005/021570
HN
I-l
wherein:
G is selected from the group consisting of:
-C(0)-R M ,
a-aminoacyl,
a-aminoacyl-a-aminoacyl,
-C(0)-0-R",
-C(0)-N(R m )R",
-C(=NY , )-R",
-CH(OH)-C(0)-OY',
-CH(OCi-4alkyl)Y 0j
-CH 2 Yi, and
-CH(CH 3 )Y i;
R" and R 1 " are independently selected from the group consisting of Cmo alkyl,
C3-7 cycloalkyl, and benzyl, each of which may be unsubstituted or substituted by one or
more substitutents selected from the group consisting of halogen, hydroxy, nitro, cyano,
carboxy, C1-6 alkyl, C M alkoxy, aryl, heteroaryl, arylCi^ alkylenyl,
heteroarylC M alkylenyl, haloC M alkylenyl, haloCi^ alkoxy, -0-C(0)-CH 3 , -C(0)-0-CH 3 ,
-C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso that R m can also
be hydrogen;
a-aminoacyl is an acyl group derived from an amino acid selected from the group
consisting of racemic, D-, and L-amino acids;
Y' is selected from the group consisting of hydrogen, Ci_6 alkyl, and benzyl;
Yo is selected from the group consisting of Ci_6 alkyl, carboxyCi_6 alkylenyl,
aminoCi_4 alkylenyl, mono-N-Ci.6 alkylaminoCi-4 alkylenyl, and
di-N,N-C\-6 alkylaminoCi-4 alkylenyl;
Yi is selected from the group consisting of mono-TV-Ci^alkylamino,
di-7/,7V-Ci>6alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and
36
WO 2006/065280
PCT/US2005/021570
4-CMalkylpiperazin-l-yl; and
R A , R B , X', Ri, and R 2 are as defined in Formula I above;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms "alkyl," "alkenyl," "alkynyl" and the prefix "alk-" are
5 inclusive of both straight chain and branched chain groups and of cyclic groups, e.g.,
cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to
20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl
groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a
total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4
10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3
to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl,
cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted
bornyl, norbornyl, and norbornenyL
Unless otherwise specified, "alkylene," "alkenylene," and "alkynylene" are the
15 divalent forms of the "alkyl," "alkenyl," and "alkynyl" groups defined above. The terms,
"alkylenyl," "alkenylenyl," and "alkynylenyl" are use when "alkylene," "alkenylene," and
"alkynylene," respectively, are substituted. For example, an arylalkylenyl group
comprises an alkylene moiety to which an aryl group is attached. In another example,
hydroxyalkylenyl, haloalkylenyl, and haloalkyleneoxy have the same meaning as
20 hydroxyalkyl, haloalkyl, and haloalkoxy, respectively.
The term "haloalkyl" is inclusive of groups that are substituted by one or more
halogen atoms, including perfluorinated groups. This is also true of other groups that
include the prefix "halo-." Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
25 The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
Unless otherwise indicated, the term "heteroatom" refers to the atoms O, S, or N.
The term "heteroaryl" includes aromatic rings or ring systems that contain at least
one ring heteroatom (e.g., O, S, N). In some embodiments, the term "heteroaryl" includes
30 a ring or ring system that contains 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O,
S, and N as the heteroatoms. Exemplary heteroaryl groups include furyl, thienyl, pyridyl,
quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl,
37
WO 2006/065280
PCT/US2005/021570
pyrazolyl, oxazolyl, thiazolyl, benzofiiranyl, benzothiophenyl, carbazolyl, benzoxazolyl,
pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl,
isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl,
tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
5 The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at
least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially
unsaturated derivatives of the above mentioned heteroaryl groups. In some embodiments,
the term "heterocyclyl" includes a ring or ring system that contains 2-12 carbon atoms, 1-3
rings, 1-4 heteroatoms, and O, S, and N as the heteroatoms. Exemplary heterocyclyl
10 groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-
dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,
isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4-
oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl,
dihydroisoquinolin-(l//)-yl, octahydroisoquinolin-(l#)-yl, dihydroquinolin-(2//)-yl,
1 5 octahydroquinolm-(2#)-yl, dihydro- l//-imidazolyl, 3-azabicyclo[3 .2.2]non-3-yl, and the
like.
The term "heterocyclyl" includes bicylic and tricyclic heterocyclic ring systems.
Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can
include, in addition to a saturated or partially saturated ring, an aromatic ring, for example,
20 a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings
joined by two spiro atoms.
When "heterocyclyl" contains a nitrogen atom, the point of attachment of the
heterocyclyl group may be the nitrogen atom.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent forms
25 of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. The terms,
"arylenyl," "heteroarylenyl," and "heterocyclylenyl" are used when "arylene,"
"heteroarylene," and "heterocyclylene," respectively, are substituted. For example, an
alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
The term "fused aryl ring" includes fused carbocyclic aromatic rings or ring
30 systems. Examples of fused aryl rings include benzo, naphtho, fluoreno, and indeno.
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The term "fused heteroaryl ring" includes the fused forms of 5 or 6 membered
aromatic rings that contain one heteroatom selected from S and N. Examples of fused
heteroaryl rings include pyrido and thieno.
The term "fused 5 to 7 membered saturated ring" includes rings which are fully
5 saturated except for the bond where the ring is fused, for example a cyclohexene ring and
a tetrahydropyridine ring (when one nitrogen atom is present).
When a group (or substituent or variable) is present more than once in any Formula
described herein, each group (or substituent or variable) is independently selected, whether
explicitly stated or not. For example, for the formula -C(0)-N(Rg)2- each R 8 group is
10 independently selected. In another example, when two R' groups are present, each R'
group is independently selected. In a further example, when more than one R' group is
present and each R' group contains one or more Rg groups, then each R' group is
independently selected, and each Rg group is independently selected.
The invention is inclusive of the compounds described herein in any of their
15 pharmaceutically acceptable forms, including isomers (e.g., diastereomers and
enantiomers), salts, solvates, polymorphs, prodrugs, and the like. In particular, if a
compound is optically active, the invention specifically includes each of the compound's
enantiomers as well as racemic mixtures of the enantiomers. It should be understood that
the term "compound" includes any or all of such forms, whether explicitly stated or not
20 (although at times, "salts" are explicitly stated).
The term "prodrug" means a compound that can be transformed in vivo to yield an
immune response modifying compound in any of the salt, solvated, polymorphic, or
isomeric forms described above. The prodrug, itself, may be an immune response
modifying compound in any of the salt, solvated, polymorphic, or isomeric forms
25 described above. The transformation may occur by vaious mechanisms, such as through a
chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic
biotransformation. A discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series,
and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
30 Pharmaceutical Association and Pergamon Press, 1987.
For any of the compounds presented herein, each one of the following variables
(e.g., X', Ri, R\ R 2 , X, Y, Ra, n, and so on) in any of its embodiments can be combined
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with any one or more of the other variables in any of their embodiments and associated
with any one of the formulas described herein, as would be understood by one of skill in
the art. Each of the resulting combinations of variables is an embodiment of the present
invention.
For certain embodiments of Formula I or 1-1, R A and R B taken together form a
fused aryl ring that is unsubstituted or substituted by one or more Ra groups. For certain
of these embodiments, the fused aryl ring is unsubstituted.
For certain embodiments of Formula I or 1-1, R A and Rb taken together form a
fused 5 to 7 membered saturated ring that is unsubstituted or substituted by one or more Re
groups. In certain of these embodiments the ring is unsubstituted.
For certain embodiments of Formula I or 1-1, R A and R B taken together form a
fused heteroaryl ring that is unsubstituted or substituted by one or more Rb groups. For
certain of these embodiments the fused heteroaryl ring is unsubstituted. In certain
embodiments, the ring is pyrido.
For certain embodiments of Formula I or 1-1, R A and R B taken together form a
fused 5 to 7 membered saturated ring containing one heteroatom selected from the group
consisting of N and S, wherein the ring is unsubstituted or substituted by one or more Re
groups. For certain of these embodiments, the ring is unsubstituted. In certain
embodiments, the ring is tetrahydropyrido. In certain of these embodiments, the ring is
wherein the highlighted bond indicates the position where the ring is fused.
For certain embodiments of Formula II, R A i and R B i are independently selected
from the group consisting of hydrogen and alkyl.
For certain embodiments of Formula n, R A i and R B i are each methyl.
For certain embodiments, including any one of the above embodiments of Formula
IK, Formula IV, or Formula X, n is 0.
For certain embodiments, the compound selected from the group consisting of
Formulas V, VI, VTI, and VIE, or a pharmaceutical^ acceptable salt thereof is the
compound of Formula V or a pharmaceutical^ acceptable salt thereof.
For certain embodiments, the compound selected from the group consisting of
Formulas Ka, DCb, IXc, and DCd, or a pharmaceutical^ acceptable salt thereof is the
compound of Formula IXa or a pharmaceutically acceptable salt thereof.
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For certain embodiments, including any one of the above embodiments of
Formulas V, VI, VII, VHI, IXa, IXb, DCc, and/or IXd, m is 0.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, II, III, IV, V, VI, VII, Vm, X, or Ka-d, X' is Cm alkylene. For certain of
these embodiments, X' is -CH2-. For certain of these embodiments, X f is -CH2CH2-.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, II, HI, IV, V, VI, VII, VIE, X, or Ka-d, Ri is selected from the group
consisting of:
alkoxyalkylenyl, and arylalkylenyl.
For certain embodiments, including any one of the above embodiments of
Formulas I, M, H, HI, IV, V, VI, VII, VIE, X, or IXa-d which does not exclude this
definition, Ri is selected from the group consisting of:
R'
R , R , and R ;
each R a is independently selected from the group consisting of fluorine, alkyl,
haloalkyl, alkoxy, and -N(R9)2; and
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each R.8 is independently selected from the group consisting of hydrogen, alkyl,
alkoxyalkylenyl, and arylalkylenyl.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, II, m, IV, V, VI, VII, VIE, X, or IXa-d which does not exclude this
definition, Ri is selected from the group consisting of
* N -if -i » n
R ' and R . For certain of these embodiments, Ri is R .
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, H, III, IV, V, VI, VII, VTE, X, or IXa-d which does not exclude this
definition, Ri is selected from the group consisting of
R'
-C(R 93 ) 2 -N^N R.rY >-J 12
K D' V J c R,
K , ,and d . For certain of these
embodiments, R9a is hydrogen. For certain of these embodiments, Ri is
R ' R'
rr° H3C-V6
CH
or 3 . For certain of these embodiments, Ri is
R'
For certain embodiments, including any one of the above embodiments of
Formulas 1,1-1, H, in, IV, V, VI, VII, VIII, X, or IXa-d which does not exclude this
definition, Ri is
N
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For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, H, HI, IV, V, VI, VII, VIE, X, or IXa-d, R f is selected from the group
consisting of alkyl, aryl, and heteroaryl, each of which is xmsubstituted or substituted by
one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, and
5 haloalkyl. For certain of these embodiments, R 1 is selected from the group consisting of
methyl; butyl; phenyl which is unsubstituted or substituted by one or more substituents
selected from the group consisting of fluorine and trifluoromethyl; and 3-pyridyl. For
certain of these embodiments, R' is selected from the group consisting of methyl; phenyl
which is unsubstituted or substituted by one or more substituents selected from the group
10 consisting of fluorine and trifluoromethyl; and 3-pyridyl.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, II, HI, IV, V, VI, VII, VIE, X, or IXa-d, R 2 is hydrogen; alkoxyalkylenyl;
hydroxyalkylenyl; haloalkylenyl; heterocyclylalkylenyl that is unsubstituted or substituted
by one or more substituents selected from the group consisting of methyl, hydroxy,
15 hydroxymethyl, and dimethylamino; -R4; -X-R4; or -X-Y-R4; wherein
X is C1-2 alkylene optionally terminated by heterocyclylene;
Y is -S(0)o- 2 -, -S(0) 2 -N(R 8 )-, -C(R«)-, -C^-O-, -OC(R 6 )-, -0-C(0)-0-,
-N(R 8 )-Q-, -C(R*)-N(R8)-, -O-CCR^-NCRg)-, or -C(R 6 )-N(OR 9 )s wherein
R 8 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl,
20 and hydroxyalkylenyl; and
R4 is alkyl that is unsubstituted or substituted by one or more substituents selected
from the group consisting of hydroxy and cyano, aryl; or heterocyclyl that is unsubstituted
or substituted by alkyl with the proviso that when Y is -C(R<s)-0- or -C(R6)-N(R 8 )-, then
R4 may also be hydrogen.
25 For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, II, in, IV, V, VI, VII, Vm, X, or IXa-d, R 2 is hydrogen, alkoxyalkylenyl,
hydroxyalkylenyl, -R4, -X-R4, or -X-Y-R4; wherein
Xis C1-2 alkylene;
Y is -S(0)o- 2 -, -S(0) 2 -N(R 8 )-, -C^)-, -C(R<0-O-, -OC(R6)-, -0-C(0)-0-,
30 -N(R 8 )-Q-, -C(R6)-N(Rg)-, -0-C(R6)-N(Rs)-, or -C(R6>N(OR 9 )-; and
R4 is alkyl.
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For certain of these embodiments, R 8 is selected from the group consisting of hydrogen,
alkyl, and arylalkylenyl.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, H, m, IV, V, VI, VII, VIII, X, or DCa-d, R 2 is hydrogen, C M alkyl,
5 Cm alkyl-O-Ci-4 alkylenyl, or hydroxyCi-4 alkylenyl. For certain of these embodiments,
R 2 is methyl, ethyl, /i-propyl, w-butyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, or
2-hydroxyethyl.
For certain embodiments, including any one of the above embodiments of
Formulas 1, 1-1, H, m, IV, V, VI, VII, Vffl, X, or Dta-d which does not exclude this
10 definition, R 2 is methyl, ethyl, H-propyl, w-butyl, ethoxymethyl, 2-methoxyethyl,
hydroxymethyl, 2-hydroxyethyl, or fluoromethyl.
For certain embodiments, the present invention provides a pharmaceutical
composition comprising a therapeutically effective amount of a compound or salt of any
one of the above embodiments of Formulas 1, 1-1, II, m, IV, V, VI, VII, VIII, and IXa-d
1 5 and a pharmaceutical^ acceptable carrier.
For certain embodiments, the present invention provides a method of inducing
cytokine biosynthesis in an animal comprising administering an effective amount of a
compound or salt of any one of the above embodiments of Formulas 1, 1-1, n, HI, IV, V,
VI, VH, VHI, and DCa-d or a pharmaceutical composition of any one of the above
20 embodiments of Formulas 1, 1-1, H, HI, IV, V, VI, VII, VIE, and IXa-d to the animal
For certain embodiments, the present invention provides a method of treating a
viral disease in an animal in need thereof comprising administering a therapeutically
effective amount of a compound or salt of any one of the above embodiments of Formulas
1, 1-1, II, in, IV, V, VI, VII, VIE, and IXa-d or a pharmaceutical composition of any one
25 of the above embodiments of Formulas 1, 1-1, H, m, IV, V, VI, VH, Vffl, and IXa-d to the
animal.
For certain embodiments, the present invention provides a method of treating a
neoplastic disease in an animal in need thereof comprising administering a therapeutically
effective amount of a compound or salt of any one of the above embodiments of Formulas
30 1, 1-1, II, IE, IV, V, VI, VII, VIH, and IXa-d or a pharmaceutical composition of any one
of the above embodiments of Formulas 1, 1-1, n, IE, IV, V, VI, VH, Vffl, and IXa-d to the
animal.
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For certain embodiments, R a is selected from the group consisting of halogen,
alkyl, haloalkyl, alkoxy, and -N(R 9 ) 2 .
For certain embodiments, R a is selected from the group consisting of fluorine,
alkyl, haloalkyl, alkoxy, and -N(R 9 )2-
For certain embodiments, Rb is selected from the group consisting of halogen,
hydroxy, alkyl, haloalkyl, alkoxy, and -N(R9) 2 .
For certain embodiments, R b is selected from the group consisting of halogen,
hydroxy, alkyl, and alkoxy.
For certain embodiments, R b is hydroxy.
For certain embodiments, Re is selected from the group consisting of halogen,
hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2-
For certain embodiments, Re is selected from the group consisting of halogen,
hydroxy, alkyl, and alkoxy.
For certain embodiments, R A i and R B i are each independently selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 ) 2 .
For certain embodiments, R A i and R B i are each independently selected from the
group consisting of hydrogen and alkyl.
For certain embodiments, R A i and R B i are each methyl.
For certain embodiments, Ri is selected from the group consisting of:
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For certain embodiments, R\ is selected from the group consisting of:
n ^O R'
y -A _^ v? vr
R . R' N' U N'° R' R' O-N
9 9 9 9 > 9
R'
// Q
, , \ R' — "\ r .^O . R„
R' R,, A' X R* W
> » »
R'
-C(R 9a ) 2 -N^N
R n ^
R 12
, and
R ° R d
For certain embodiments, Ri is selected from the group consisting of:
R'
> ft ;
* \ R' , W >and R < R d
For certain embodiments, Ri is selected from the group consisting of:
R'
M H r.^o
R> , R \and R ' ;
For certain embodiments, Ri is selected from the group consisting of:
r -i r
R ' and R ' .
For certain embodiments, R\ is
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10
ft
R'
For certain embodiments, Ri is selected from the group consisting of:
R'
11 i
-C(R 9a ) 2 -N N R
R^T~° V R "
R1 , ,and R "
For certain embodiments, Ri is
12
d
^ or CH 3.
For certain embodiments, Ri is
R'
For certain embodiments, Ri is selected from the group consisting of:
* y^* -*v* "Vps
N'° N'° R' R' O-N R" R,i A' ,
> > > , - — , and
R 12
N'
R 1 R i-7^
R'
For certain embodiments, Ri is N
For certain embodiments, R2 is selected from the group consisting of:
-R4,
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-X-R4,
-X-Y-R4, and
-X-R 5 .
For certain embodiments, R2 is hydrogen; alkoxyalkylenyl; hydroxyalkylenyl;
5 haloalkylenyl; heterocyclylalkylenyl that is unsubstituted or substituted by one or more
substituents selected from the group consisting of methyl, hydroxy, hydroxymethyl, and
dimethylamino; -R4; -X-R4; or -X-Y-R4. In certain of these embodiments, X is
C1-2 alkylene optionally terminated by heterocyclylene; Y is -S(0)o-2-> -S(0)2-N(Rg)-,
-C(R6>, -C(R6>0-, -0-C(R6>, -0-C(0)-0-, -N^-Q-, -C(R^)-N(R 8 )-, -0-C(R6)-N(Rs)-,
10 or -C(R6)-N(OR9)-; and R4 is alkyl that is unsubstituted or substituted by one or more
substituents selected from the group consisting of hydroxy and cyano, aryl; or heterocyclyl
that is unsubstituted or substituted by alkyl with the proviso that when Y is -C(R6)-0- or
-C(R6)-N(Rs)-, then R4 may also be hydrogen. In certain of these embodiments, R 8 is
selected from the group consisting of hydrogen, alkyl, arylalkylenyl, and
15 hydroxyalkylenyl. In certain of these embodiments, R 8 is selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl.
For certain embodiments, R2 is hydrogen, alkoxyalkylenyl, hydroxyalkylenyl, -R4,
-X-R4, or -X-Y-R4; wherein: X is C U2 alkylene; Y is -S(O) 0 . 2 -, -S(0) 2 -N(R 8 >, -C^)-,
-C(R6)-0-, -0-C(R6>, -0-C(0)-0-, -N(R 8 )-Q-, -C(R6>N(R 8 )-, -0-C(R6)-N(R 8 )-, or
20 -C(R6)-N(OR 9 )-; and R4 is alkyl. In certain of these embodiments, R 8 is selected from the
group consisting of hydrogen, alkyl, arylalkylenyl, and hydroxyalkylenyl. In certain of
these embodiments, Rs is selected from the group consisting of hydrogen, alkyl, and
arylalkylenyl.
For certain embodiments, R 2 is hydrogen, Cm alkyl, C1-4 alkyl-O-Ci-4 alkylenyl, or
25 hydroxyCi-4 alkylenyl
For certain embodiments, R 2 is methyl, ethyl, w-propyl, 72-butyl, ethoxymethyl, 2-
methoxyethyl, hydroxymethyl, or 2-hydroxyethyl.
For certain embodiments, R2 is methyl, ethyl, n-propyl, n-butyl, ethoxymethyl, 2-
methoxyethyl, hydroxymethyl, 2-hydroxyethyl, or fluoromethyl.
30 For certain embodiments, R4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
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wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,
heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and
heterocyclyl groups are unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino,
alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl,
alkynyl, and heterocyclyl, oxo.
For certain embodiments, R4 is alkyl.
For certain embodiments, R 5 is selected from the group consisting of:
For certain embodiments, R6 is selected from the group consisting of =0 and =S.
For certain embodiments, R 6 is =0.
For certain embodiments, R 7 is C2-7 alkylene.
alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl.
For certain embodiments, R 8 is selected from the group consisting of hydrogen,
alkyl, alkoxyalkylenyl, and arylalkylenyl.
For certain embodiments, R 8 is selected from the group consisting of hydrogen and
alkyl.
For certain embodiments, R 8 is hydrogen.
For certain embodiments, R 9 is selected from the group consisting of hydrogen and
For certain embodiments, R 9a is selected from the group consisting of hydrogen
and Cm alkyl.
For certain embodiments, R 9a is hydrogen.
For certain embodiments, R 9a is methyl.
For certain embodiments, Rio is C3-8 alkylene.
For certain embodiments, R u is Ci- 6 alkylene or C 2 -6 alkenylene, wherein the
alkylene or alkenylene is optionally interrupted by one heteroatom; and wherein the total
, and
For certain embodiments, Rs is selected from the group consisting of hydrogen,
alkyl.
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number of atoms in the ring which includes Rj i is 4 to 9. For certain of these
embodiments, Ri i is Ci-6 alkylene. For certain of these embodiments, the total number of
atoms in the ring which includes Rn is 5.
For certain embodiments, R12 is selected from the group consisting of a bond,
5 Ci_ 5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally
interrupted by one heteroatom; and wherein the total number of atoms in the ring which
includes R12 is 4 to 9.
For certain embodiments, R' is selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl,
10 heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl,
heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more
substituents selected from the group consisting of hydroxy, alkyl, haloalkyl, hydroxyalkyl,
alkoxy, dialkylamino, -S(O) 0 . 2 -alkyl, -S(O) 0 - 2 -aryl, -NH-S(0) 2 -alkyl, -NH-S(0) 2 -aryl,
haloalkoxy, halogen, nitrile, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
15 -C(0)-0-alkyl, «C(0)-N(R 8 ) 2 , -N(R 8 )-C(0)-alkyl, -0-(CO)-alkyl, and -C(0)-alkyl.
For certain embodiments, R is selected from the group consisting of alkyl, aryl,
and heteroaryl, each of which is unsubstituted or substituted by one or more substituents
selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl.
For certain embodiments, R is selected from the group consisting of methyl; butyl;
20 phenyl which is unsubstituted or substituted by one or more substituents selected from the
group consisting of fluorine and trifluoromethyl; and 3-pyridyl.
For certain embodiments, R is selected from the group consisting of methyl;
phenyl which is unsubstituted or substituted by one or more substituents selected from the
group consisting of fluorine and trifluoromethyl; and 3-pyridyl.
25 For certain embodiments, R is methyl.
For certain embodiments, Rc and Rd are independently selected from the group
consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio,
and -N(R9) 2 ; or Rc and R<j can join to form a fused aryl ring or fused 5-10 membered
heteroaryl ring containing one to four heteroatoms.
30 For certain embodiments, Rc and Rd are each hydrogen.
For certain embodiments, Rc and Rd join to form a benzo ring.
For certain embodiments, A is selected from the group consisting of -0-, -C(O)-,
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-S(O) 0 -2-, -CH 2 -, and -NOR4)-.
For certain embodiments, A is -0-.
For certain embodiments, A' is selected from the group consisting of -0-, -S(O) 0 -2-,
-N(-Q-R4)-, and -C(R 9a ) 2 -.
For certain embodiments, A 1 is -C(R 9a )2-.
For certain embodiments, Q is selected from the group consisting of a bond,
-C(R 6 )-, -C(R«>C(R«>, -S(0) 2 -, and -S(0) 2 -N(R 8 >.
For certain embodiments, Q is -C(O)-, -S(0) 2 -, or -C(0)-NH-.
For certain embodiments, V is selected from the group consisting of -C(R$)-,
-0-C(R 6 )-, and -S(0) 2 -.
For certain embodiments, V is -C(O)-.
For certain embodiments, X is selected from the group consisting of alkylene,
alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene,
alkenylene, and alkynylene groups are optionally interrupted or terminated by arylene,
heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups.
For certain embodiments, X is C1-4 alkylene.
For certain embodiments, X is C\. 2 alkylene.
For certain embodiments, X 1 is selected from the group consisting of -CH(R 9 >,
-CH(R 9 )-alkylene-, and -CH(R 9 )-alkenylene-.
For certain embodiments, X f is C1-4 alkylene.
For certain embodiments, X 1 is -CH 2 -.
For certain embodiments, Y is selected from the group consisting of -S(0)o-2-,
-S(0) 2 -N(R 8 >, -C^)-, -C(R<0-O-, -0-C(R6K -0-C(0)-0-, -N(Rs)-Q-, -C(R6)-N(R 8 )-,
For certain embodiments, Y is -S(O) 0 -2-, -S(0) 2 -N(R8)-, -C(R6)-, -C(R6)-0-,
-0>C(R 6 )-, -0-C(0)-0-, -N(R 8 )-Q-, -C^-NCRg)-, -0-C(R6)-N(R 8 )-, or -C(R 6 )-N(OR 9 )-.
For certain embodiments, a and b are each independently an integer from 1 to 6
with the proviso that a + b is < 7.
, and
—V-N
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For certain embodiments, a and b are each independently 1 to 3.
For certain embodiments, a and b are each 2.
For certain embodiments, n is an integer from 0 to 4.
For certain embodiments, n is 0 or 1.
5 For certain embodiments, n is 0.
For certain embodiments, m is an integer from 0 to 3.
For certain embodiments, m is 0 or 1 .
For certain embodiments, m is 0.
For certain embodiments of the compounds of Formulas 1, 1-1, n, HI, IV, V, VI,
10 VII, VIH, X, and IXa-d the -NH 2 group can be replaced by an -NH-G group, as shown in
the compound of Formula M, to form prodrugs. In such embodiments, G is selected from
the group consisting of -C(0)-R M , a-aminoacyl, a-aminoacyl-a-aminoacyl, -C(0)-0-R",
-C(0)-N(R'")R", -C(=NY')-R", -CH(OH)-C(0)-OY', -CH(OC M alkyl) Y 0 , -CH 2 Y l5 and
-CH(CH 3 )Yi. In some embodiments G is selected from the group consisting of -C(0>R",
15 a-aminoacyl, a-aminoacyl-a-aminoacyl, and -C(0)-0-R". Preferably, R ,f and R m are
independently selected from the group consisting of C M0 alkyl, C 3 . 7 cycloalkyl, and
benzyl, each of which may be unsubstituted or substituted by one or more substitutents
selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, d-6 alkyl,
Cm alkoxy, aryl, heteroaryl, arylCi-4 alkylenyl, heteroarylCi-4 alkylenyl,
20 haloC M alkylenyl, haloC M alkoxy, -0-C(0)-CH 3 , -C(0)-0-CH 3 , -C(0)-NH 2 ,
-0-CH 2 -C(0)-NH 2 , -NH 2 , and -^S(0) 2 -NH 2 . R"' may also be hydrogen. Preferably, a-
aminoacyl is an acyl group derived from an amino acid selected from the group consisting
of racemic, D-, and L-amino acids. Preferably, Y' is selected from the group consisting of
hydrogen, Ci_ 6 alkyl, and benzyl. Preferably, Y 0 is selected from the group consisting of
25 C1-6 alkyl, carboxyCi^ alkylenyl, aminoCi^ alkylenyl,
mono-A^-Ci-6 alkylaminoC M alkylenyl, and di-N,N-Ci- 6 alkylaminoC M alkylenyl.
Preferably, Y! is selected from the group consisting of mono-N-Ci-6 alkylamino, di-N,N-
Ci-6 alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and 4-C M alkylpiperazin-
1-yL
30 For certain embodiments, including any one of the above embodiments containing
-NH-G, G is -C(0)-R", a-aminoacyl, a-aminoacyl-a-aminoacyl, or -C(0)-0-R".
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Preparation of the Compounds
Compounds of the invention may be synthesized by synthetic routes that include
processes analogous to those well known in the chemical arts, particularly in light of the
description contained herein. The starting materials are generally available from
5 commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are
readily prepared using methods well known to those skilled in the art (e.g. prepared by
methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic
Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth-
Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v 1-
10 6, Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming,
Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); or
Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin,
Germany, including supplements (also available via the Beilstein online database)).
For illustrative purposes, the reaction schemes depicted below provide potential
15 routes for synthesizing the compounds of the present invention as well as key
intermediates. For more detailed description of the individual reaction steps, see the
EXAMPLES section below. Those skilled in the art will appreciate that other synthetic
routes may be used to synthesize the compounds of the invention. Although specific
starting materials and reagents are depicted in the reaction schemes and discussed below,
20 other starting materials and reagents can be easily substituted to provide a variety of
derivatives and/or reaction conditions. In addition, many of the compounds prepared by
the methods described below can be further modified in light of this disclosure using
conventional methods well known to those skilled in the art.
In the preparation of compounds of the invention it may sometimes be necessary to
25 protect a particular functionality while reacting other functional groups on an intermediate.
The need for such protection will vary depending on the nature of the particular functional
group and the conditions of the reaction step. Suitable amino protecting groups include
acetyl, trifluoroacetyl, terf-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-
fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and
30 silyl groups such as the tert-butyl dimethylsilyl group. For a general description of
protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, John Wiley & Sons, New York, USA, 1991.
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Conventional methods and techniques of separation and purification can be used to
isolate compounds of the invention or pharmaceutically acceptable salts thereof, as well as
various intermediates related thereto. Such techniques may include, for example, all types
of chromatography (high performance liquid chromatography (HPLC), column
5 chromatography using common absorbents such as silica gel, and thin layer
chromatography, recrystallization, and differential (i.e., liquid-liquid) extraction
techniques.
Compounds of the invention are prepared according to Reaction Scheme I, wherein
Ra, R\ R2, X', and n are as defined above; the bond represented by the dotted line can
10 either be present or absent; and Ri a is a subset of Ri that includes the rings:
R and R ' , wherein R ! is as defined above. In step (1) of Reaction
Scheme I, an amine of Formula NH 2 -X -CH=CH 2 or NH 2 -X-C=C-H is combined with a
2,4-dichloro-3-nitroquinoline of Formula XV. This reaction is conveniently carried out by
adding the amine to a solution of a compound of Formula XV in the presence of a base
1 5 such as triethylamine. The reaction is carried out in a suitable solvent, such as
dichloromethane, chloroform, or DMF and may be carried out at room temperature, a sub-
ambient temperature such as 0 0 C, or an elevated temperature such as the reflux
temperature of the solvent. Several compounds of Formula XV are known and can be
made by known methods. See, for example, U.S. Patent No. 4,689,338 (Gerster) and
20 4,988,815 (Andre et al). Amines of the Formula NH 2 -X'-CH=CH 2 or NH 2 -X'-C=C-H are
commercially available or can be readily prepared by known methods.
The resultant compound of Formula XVI is reduced in step (2) of Reaction Scheme
I to provide a 2-chloroquinoline-3,4-diamine of Formula XVII. Step (2) is conveniently
carried out using a one- or two-phase sodium dithionite reduction. The reaction is
25 conveniently carried out using the conditions described by Park, K. K.; Oh, C. H.; and
Joung, W. K.; Tetrahedron Lett., 34, pp. 7445-7446 (1993) by adding sodium dithionite to
a compound of Formula XVI in a mixture of dichloromethane and water at room
temperature in the presence of potassium carbonate and ethyl viologen dibromide, ethyl
viologen diiodide, or l,r-di-;z-octyl-4,4 , -bipyridinium dibromide. Alternatively, the
30 reduction can be carried out by adding an aqueous solution of sodium dithionite to a
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compound of Formula XVI in a suitable solvent or solvent mixture such as
ethandl/acetonitrile.
In step (3) of Reaction Scheme I, a 2-chloroquinoline-3,4-diamine of Formula
XVII is treated with a carboxylic acid equivalent to provide a l#-imidazo[4,5-c]quinoline
5 of Formula XVIII. Suitable carboxylic acid equivalents include orthoesters of Formula
R 2 C(0-alkyl) 3 , 1,1-dialkoxyalkyl alkanoates of Formula R 2 C(0-alkyl) 2 (0-C(0)-alkyl),
and acid chlorides of Formula R 2 C(0)C1. The selection of the carboxylic acid equivalent
is determined by the desired substituent at R 2 . For example, triethyl orthoformate will
provide a compound where R 2 is hydrogen, and trimethyl orthovalerate will provide a
10 compound where R 2 is a butyl group. The reaction is conveniently carried out by adding
the carboxylic acid equivalent to a quinoline-3,4-diamine of Formula XVII in a suitable
solvent such as toluene. Optionally, catalytic pyridine hydrochloride or pyridinium p-
toluenesulfonate can be added. The reaction is carried out at a temperature high enough to
drive off alcohol or water formed during the reaction. Conveniently, a Dean-Stark trap
15 can be used to collect the volatiles.
Alternatively, step (3) can be carried out in two steps when an acid chloride of
Formula R 2 C(0)C1 is used as the carboxylic acid equivalent. The first step is conveniently
carried out by adding the acid chloride to a solution of a quinoline-3,4-diamine of Formula
XVII in a suitable solvent such as dichloromethane to afford an amide. Optionally, a
20 tertiary amine such as triethylamine, pyridine, or catalytic 4-dimethylaminopyridine
(DMAP) can be added. The reaction can be carried out at or below room temperature.
The amide product can be isolated and optionally purified using conventional techniques
before it is heated and cyclized to provide a l#-imidazo[4,5-c]quinoline of Formula
XVIII. The cyclization reaction is conveniently carried out in a solvent such as ethanol or
25 methanol or a solvent mixture such as ethanol/water in the presence of a base such as
triethylamine, potassium carbonate, or sodium hydroxide and may be carried out at an
elevated temperature, such as the reflux temperature of the solvent.
In step (4) of Reaction Scheme I, the alkene or alkyne group of a compound of
Formula XVIII undergoes a cycloaddition reaction with a nitrile oxide formed from an cc-
30 chloroaldoxime of Formula XIX, to provide a isoxazole or dihydroisoxazole-substituted
li/-imidazo[4,5-c]quinoline of Formula Xa, a subgenus of Formula X. oc-
Chloroaldoximes of Formula XIX can be prepared by treating an aldoxime of Formula
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R'(H)C=N-OH with iV-chlorosuccinimide in a suitable solvent such as N,N-
dimethylformamide (DMF). The reaction may be carried out initially below room
temperature, at 0 °C for example, and then heated at an elevated temperature in the range
of 40 °C to 50 °C. Aldoximes of Formula R'(H)C=N-OH are commercially available or
can be prepared from aldehydes by methods well known to one skilled in the art. The
resulting cc-chloroaldoxime of Formula XIX can be isolated using conventional methods
before it is combined with a compound of Formula XVIII in the presence of a base such as
triethylamine to generate a nitrile oxide in situ and effect the cycloaddition reaction. The
reaction with an a-chloroaldoxime can be carried out at room temperature in a suitable
solvent such as dichloromethane.
In step (5) of Reaction Scheme I, a compound of Formula Xa is aminated to
provide a 17/-imidazo[4,5-c]quinolin-4-amine of Formula Ula, a subgenus of Formulas I
and HI. The reaction is conveniently carried out by adding a solution of ammonia in a
suitable solvent such as methanol to a compound of Formula Xa and heating the reaction
at an elevated temperature such as 1 50 °C. The reaction may be carried out in a pressure
vessel.
Reaction Scheme I
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Compounds of the invention can be prepared according to Reaction Scheme II,
wherein R A , Rb, X', R2, and R Ja are as defined above. In step (1) of Reaction Scheme n, a
compound of Formula XX is reacted with an amino alcohol of the Formula H 2 N-X'-OH to
form a compound of Formula XXL The reaction is conveniently carried out according to
5 the method described in step (1) of Reaction Scheme I. Many 2,4-dichloro-3-
nitropyridines of the Formula XX are known and can be readily prepared using known
synthetic methods. See, for example, Dellaria et al, U.S. Pat. No. 6,525,064 and the
references cited therein. Many 2,4-dichloro-3-nitroquinolines are also known and can be
prepared by known methods as described in Reaction Scheme I. Related routes to
10 tetrahydroquinolines of Formula XXI are known; see, for example, U.S. Patent Nos.
5,352,784 (Nikolaides et al) and 6,670,372 (Charles et al).
In step (2) of Reaction Scheme II a compound of Formula XXI is reacted with an
alkali metal azide to provide a tetrazole of Formula XXII. The reaction can be carried out
by combining the compound of Formula XXI with an alkali metal azide, for example,
15 sodium azide, in a suitable solvent such as acetonitrile/water, preferably 90/10
acetonitrile/water, in the presence of cerium (III) chloride, preferably cerium (HI) chloride
heptahydrate. Optionally, the reaction can be carried out with heating, for example, at the
reflux temperature. Alternatively, the reaction can be carried out by combining the
compound of Formula XXI with an alkali metal azide, for example, sodium azide, in a
20 suitable solvent such as DMF and heating, for example in the range of 50 °C to 60 °C,
optionally in the presence of ammonium chloride. Other related routes to
imidazonaphthyridines of Fomula XXII have been reported; see, for example, U.S. Patent
No. 6,194,425 (Gerster et al).
In step (3) of Reaction Scheme II, the nitro group of the compound of Formula
25 XXII is reduced to provide a diamine of Formula XXIII. The reduction can be carried out
according to one of the methods described in step (2) of Reaction Scheme I. Alternatively,
the reduction can be carried out by hydrogenation using a heterogeneous hydrogenation
catalyst such as platinum on carbon. The hydrogenation is conveniently carried out in a
Parr apparatus in a suitable solvent such as toluene, a lower alcohol such as isopropanol or
30 ethanol, or mixtures thereof. Other suitable solvents include ethyl acetate and acetonitrile.
The reaction can be carried out at room temperature.
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In step (4) of Reaction Scheme II, a diamine of Formula XXIII is reacted with a
carboxylic acid equivalent to provide a compound of Formula XXTV. The reaction can be
carried out as described in step (3) of Reaction Scheme I. Some pyridines of Formula
XXIV are known; see, for example, U.S. Patent No. 6,797,718 (Dellaria et al).
5 In step (5) of Reaction Scheme II, the alcohol of Formula XXIV is oxidized to an
aldehyde-substituted compound of Formula XXV using conventional methods, for
example, Swern oxidation conditions. The Swern oxidation is conveniently carried out by
adding a compound of Formula XXIV followed by triethylamine to a mixture of oxalyl
chloride and dimethylsulfoxide in a suitable solvent, such as dichloromethane. The
10 reaction can be carried out at sub-ambient temperatures, such as -78 °C.
In step (6) of Reaction Scheme n, an aldehyde- substituted compound of Formula
XXV is converted to an alkenyl- or alkynyl-substituted compound of Formula XXVI. The
conversion to an alkyne is conveniently carried out by adding diethyl l-diazo-2-
oxopropylphosphonate to the aldehyde-substituted compound of Formula XXV in the
15 presence of a mild base such as potassium carbonate. The reaction is carried out in a
suitable solvent such as methanol or dichloromethane at room temperature. The aldehyde-
substituted compound of Formula XXV can be converted to an alkenyl-substituted
compound of Formula XXVI using synthetic methods well known to those skilled in the
art; such methods include the Wittig reaction.
20 In step (7) of Reaction Scheme II, the alkene or alkyne dipolarophile of Formula
XXVI undergoes a cycloaddition reaction with a nitrile oxide generated from an <x-
chloroaldoxime of Formula XIX. The reaction can be run according to the methods
described in step (4) of Reaction Scheme I to provide a product of Formula XXVII.
In step (8) of Reaction Scheme n, the tetrazole ring is removed from a compound
25 of Formula XXVII by reaction with triphenylphosphine to form an N-triphenylphosphinyl
intermediate. The reaction with triphenylphosphine can be run in a suitable solvent such
as toluene or 1,2-dichlorobenzene under an atmosphere of nitrogen with heating, for
example at the reflux temperature. The Af-triphenylphosphinyl intermediate is then
hydrolyzed to provide a compound of Formula la. The hydrolysis can be carried out by
30 general methods well known to those skilled in the art, for example, by heating in a lower
alkanol such as methanol in the presence of an acid such as hydrochloric acid.
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Reaction Scheme II
For certain embodiments, compounds of the invention are prepared according to
Reaction Scheme HI, wherein R*, R 2? X 1 , and n are as defined above, and Rib is a subset of
Ri that includes the rings:
FT
I — C(^a> 2 -N^N
I - C(Rj2 Xo N 4°
-c(r 93 ) 2 -n^n r /y° v>
R " , A'-^ ,and 0 R o , wherein R, R 9a , Rii, Ri2,
Rc, R^, and A' are as defined above. In step (1) of Reaction Scheme HI, a 1-aminoalkyl-
substituted imidazoquinoline of Formula XXVIII is converted to an imine by reaction with
a ketone or aldehyde of Formula (R')2C=0 and subsequently treated with an a-
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10
chloroaldoxime of Formula XIX. The reaction is conveniently earned out by combining
an aminoalkyl-substituted imidazoquinoline of Formula XXVIII with a ketone or aldehyde
of Formula (R'^CO,
12
at room temperature in a suitable solvent such as
dichloromethane. The reaction can optionally be carried out in the presence of magnesium
sulfate. The resulting imine is then combined with an a-chloroaldoxime of Formula XIX
according to the procedure described in step (4) of Reaction Scheme I. Some compounds
of Formula XXVIII are known; see U.S. Patent No. 6.069,149 (Nanba et al). Others can
be readily prepared by known methods.
In step (2) of Reaction Scheme m, a 4-chloro-l//-imidazo[4,5-c]quinoline is
animated to provide a heterocyclyl-substituted l//-imidazo[4,5-c]quinolin-4-amine of
Formula mb. The reaction can be carried out according to the method described in step
(5) of Reaction Scheme I.
15
Reaction Scheme III
CI
XXVIII
XXIX
An aldehyde-substituted compound of Formula XXV, shown in Reaction Scheme
II, can also be used to make compounds of the invention wherein Ri is
R'
20 or w , wherein R' is as defined above. The transformation is
conveniently carried out by converting an aldehyde of Formula XXV to an aldoxime using
methods well known to one of skill in the art, for example, by reaction with
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hydroxylaxnine hydrochloride in the presence of base such as aqueous sodium hydroxide
in a suitable solvent such as ethanol, water, or mixtures thereof The reaction can be run at
room temperature. The aldoxime can then be converted to an a-chloroaldoxime and
subsequently treated with triethylamine to generate a nitrile oxide in the presence of an
alkene of formula R-CH=CH 2 or an alkyne of formula R'-C=C-H according to the
methods described in step (4) of Reaction Scheme I. Numerous alkenes and alkynes of
these formulas are commercially available; others can be prepared by known methods.
The a-chloroaldoxime prepared by this method can also be treated with an imine
generated from an amine of formula R'-NH 2 and a compound of formula (R')2C=0,
p
.0
V 11 R 1
1 0 A 1 —' 5 or R <J using the conditions described in step (1 ) of Reaction Scheme IE
to provide a compound of the invention wherein Ri is
N y N-R'
1.
N N-R'
N ' N-R 1
O:
R< 11
R , ^-A ,or R d w . Numerous primary amines are commerci ally
available and can be used to carry out this transformation.
Aldehydes of Formula XXV can also be used to prepare compounds of the
15 invention wherein Rj is
R'
N^R'
u by first optionally converting it to a ketone using a Grignard reagent of
formula RMgHalide. Many Grignard reagents are commercially available, and their
reaction with aldehydes to prepare secondary alcohols is well known to one of skill in the
art. The secondary alcohol can then be oxidized to a ketone using one of numerous
20 methods, such as the Swern oxidation described in step (5) Reaction Scheme II. The
aldehyde of Formula XXV or the ketone prepared in this manner can be converted to an
imine and reacted with an a-chloroaldoxime of Formula XIX according to the method
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described in step (1) of Reaction Scheme HI. The method described in step (8) of
Reaction Scheme II can be used after any of these alternative methods to provide a
compound of Formula I
Certain imidazonapthyridines of the invention can be prepared according to
Reaction Scheme IV, wherein Rt>, X\ R 2 , Ri a , R 1 , and m are as defined above, and the bond
represented by the dotted line can either be present or absent. Reaction Scheme IV begins
with a 4-chloro-3-nitro[l,5]naphthyridine of Formula XXX. Compounds of Formula
XXX and their preparation are known; see, for example, U.S. Patents Nos. 6,194,425
(Gerster) and 6,518,280 (Gerster). Steps (1), (2), (3), and (4) of Reaction Scheme IV can
be carried out according to the methods described in steps (1), (4), (2), and (3),
respectively, of Reaction Scheme I to provide a substituted l#-imidazo[4,5-
c][l,5]naphthyridine of Formula XXXTV. Alternatively, step (3) of Reaction Scheme IV
can be carried out by hydrogenation as described in step (3) of Reaction Scheme II.
In step (5) of Reaction Scheme IV, a l/^imidazo^S-^fl^lnaphthyridine of
Formula XXXTV is oxidized to provide a ljf/-imidazo[4,5-c][l ? 5]naphthyridine-5A^-oxide
of Formula XXXV using a conventional oxidizing agent capable of forming N-oxides.
The reaction is conveniently carried out by adding 3-chloroperoxybenzoic acid to a
solution of a compound of Formula XXXTV in a solvent such as dichloromethane or
chloroform. The reaction can be carried out at room temperature.
In step (6) of Reaction Scheme TV, a 5N-oxide of Formula XXXV is aminated to
provide a li/-imidazo[4,5-c][l,5]napthyridin-4-amine of Formula Va, a subgenus of
Formulas I and V. Step (6) can be carried out by the activation of an N-oxide of Formula
XXXV by conversion to an ester and then reacting the ester with an animating agent.
Suitable activating agents include alkyl- or arylsulfonyl chlorides such as benzenesulfonyl
chloride, methanesulfonyl chloride, or /?-toluenesulfonyl chloride. Suitable aminating
agents include ammonia, in the form of ammonium hydroxide, for example, and
ammonium salts such as ammonium carbonate, ammonium bicarbonate, and ammonium
phosphate. The reaction is conveniently carried out by adding ammonium hydroxide to a
solution of the N-oxide of Formula XXXV in a suitable solvent such as dichloromethane
or chloroform and then adding /7-toluenesulfonyl chloride or benzenesulfonyl chloride.
The reaction can be carried out at ambient temperature.
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Steps (5) and (6) of Reaction Scheme IV may be carried out as a one-pot procedure
by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula XXXIV in
a solvent such as dichloromethane or chloroform and then adding ammonium hydroxide
and/?-toluenesulfonyl chloride or benzenesulfonyl chloride without isolating the TV-oxide
compound of Formula XXXV.
The amination reaction in step (6) of Reaction Scheme IV can alternatively be
carried out by treating a 5iV-oxide of Formula XXXV with trichloroacetyl isocyanate
followed by hydrolysis of the resulting intermediate to provide a compound of Formula
Va, a subgenus of Formulas I and V. The reaction is conveniently carried out in two steps
by (i) adding trichloroacetyl isocyanate to a solution of a 5N-oxide of Formula XXXV in a
solvent such as dichloromethane and stirring at ambient temperature to provide an isolable
amide intermediate. In step (ii), a solution of the intermediate in methanol is treated with
a base such as sodium methoxide or ammonium hydroxide at ambient temperature.
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Reaction Scheme IV
( R b)m R la
Va
For certain embodiments, compounds of the invention can be prepared according
5 to Reaction Scheme V, wherein R A , R B , X', R 2 , R 9a , and R lb are as defined above. In
Reaction Scheme V, an aminoalkyl-substituted compound of Formula XXXVI is
converted to a heterocyclyl-substituted compound of Formula lb according to the method
described in step (1) of Reaction Scheme m. Many compounds of Formula XXXVI are
known, including li/-imidazo[4,5-c]quinolines and 6,7,8,9"tetrahydro-l/f-imidazo[4,5-
10 c]quinolines in U.S. Patent Nos. 6,451,810 (Coleman et al) and 6,677,349 (Griesgraber),
l^-imidazo[4,5-c][l,5]naphthyridines in U.S. Patents No. 6,194,425 (Gerster), and IH-
imidazo[4,5-c]pyridines in U.S. Patents No. 6,545,016 (Dellaria et al).
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Reaction Scheme V
NH 2 R ib
XXXVI ib
Compounds of the invention can also be prepared according to Reaction Scheme
VI, wherein n is as defined above; R f is alkyl, alkoxy, or -N(R 9 >2; X' c is -CH(R 9 )- or
-CH(R 9 )-alkylene-; and R 2c and Ri c are subsets of R 2 and Ri as defined above that do not
include those substituents that one skilled in the art would recognize as being susceptible
to reduction under the acidic hydrogenation conditions of the reaction. These susceptible
groups include, for example, alkenyl and alkynyl groups and groups bearing nitro
substituents.
As shown in Reaction Scheme VI, an l#-imidazo[4,5-c]quinoline of Formula Hlf,
prepared according to the methods described in any of Reaction Schemes I through III and
V, is reduced to a 6,7,8,94e1rahydro-li7-imidazo[4,5-c]quinolin-4-aimne of Formula IVa,
a subgenus of Formulas I and IV. The reaction is conveniently carried out under
hetereogeneous hydrogenation conditions by adding platinum (IV) oxide to a solution of
the compound of Formula IQf in trifluoroacetic acid and placing the reaction under
hydrogen pressure. The reaction can be carried out on a Parr apparatus at room
temperature.
Reaction Scheme VI
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Compounds of the invention can also be prepared according to Reaction Scheme
VII, wherein Ri c , R20 Rf> X' c , and m are as defined above. In Reaction Scheme VII, a 1//-
imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula Vb, prepared as described in any one
of Reaction Schemes II, IV, and V is reduced to a 6,7,8,9-tetrahydro-l// : -imida2o[4,5-
5 c][l,5]naphthyridin-4-amine of Formula XXXVII, a subgenus of Formulas I and DCa. The
reaction is conveniently carried out using the conditions described in Reaction Scheme VI.
Reaction Scheme VII
Vb XXXVII
10
Imidazo[4,5-c]pyridines of the invention can be prepared according to Reaction
Scheme VIII, wherein R A i, Rbi> X 1 , R\ R 2 , and R ia are as defined above, the bond
represented by the dotted line can either be present or absent, and Bn is benzyl or p-
methoxybenzyl. In step (1) of Reaction Scheme VHI, a 2,4-dichloro-3-nitropyridine of
1 5 Formula XXXVIII is reacted with an amine of Formula NH 2 -X-CH==CH 2 or
NH2-X , -OC-H as described in step (1) of Reaction Scheme I. Many 2,4-dichloro-3-
nitropyridines of Formula XXXVIII are known as referenced in Reaction Scheme II.
In step (2) of Reaction Scheme VIE, the chloro group in a pyridine of Formula
XXXIX is displaced by an amine of Formula HN(Bn) 2 to provide a pyridine of Formula
20 XL. The displacement is conveniently carried out by combining an amine of Formula
HN(Bn) 2 and a compound of Formula XXXIX in a suitable solvent such as toluene or
xylenes in the presence of a base such as triethylamine and heating at an elevated
temperature such as the reflux temperature of the solvent.
In step (3) of Reaction Scheme VIE, a compound of Formula XL is reduced to
25 provide a pyridine-2,3,4-triamine of Formula XLL The reduction can be carried out as
described in step (2) of Reaction Scheme I. The reaction can be carried out using
alternative methods as described in U.S. Patent No. 5,395,937 (Nikolaides et al).
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In step (4) of Reaction Scheme VHI, a quinoline-2,3,4-triamine of Formula XLI is
cyclized to a l#-imidazo[4,5-c]pyridine of Formula XLH The reaction is carried out
according to one of the methods described in step (3) of Reaction Scheme L
In step (5) of Reaction Scheme VIII, the alkene or alkyne dipolarophile of Formula
XLII undergoes a cycloaddition reaction with a nitrile oxide generated from a <x-
chloroaldoxime of Formula XIX. The reaction can be run according to the methods
described in step (4) of Reaction Scheme I to provide a product of Formula XLIIL
In step (6) of Reaction Scheme VIII, the protecting groups are removed from the 4-
amine of a pyridine of Formula XLEQ to provide a substituted l#-imidazo[4,5-c]pyridin-
4-amine of Formula Ha, a subgenus of Formulas I and II. The deprotection is
conveniently carried out on a Parr apparatus under hydrogenolysis conditions using a
suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol.
The reaction can also be carried out by adding trifluoroacetic acid to a compound of
Formula XLHI and stirring at room temperature or heating at an elevated temperature such
as 50 °C to 70 °C.
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Reaction Scheme Vm
^1a
Ha
For some embodiments, tetrahydroquinolines of the invention can be prepared
according to Reaction Scheme IX, wherein R f , X' c , R 2c , Ru, and n are as defined above;
Boc is a ter/-butoxycarbonyl group; and PG is a hydroxy protecting group. In step (1) of
Reaction Scheme I, the hydroxy group of a substituted quinoline of Formula XLIV is
protected using conventional techniques to provide a substituted quinoline of Formula
XLV. A number of suitable protecting groups can be used; in particular, protecting groups
that would survive the reduction in step (2) are preferred. Suitable protecting groups
include but are not limited to silyl groups such as the te^butyldimethylsilyl group. The
reaction is conveniently earned out by treating the hydroxy-substituted compound of
Formula XLIV with tert-butyldimethylsilyl chloride in the presence of a base such as
triethylamine and catalytic DMAP. The reaction can be carried out in a suitable solvent
such as pyridine or dichloromethane at an elevated temperature such as 60 °C.
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Compounds of Formula XLIV are available from the method described in step (1) of
Reaction Scheme H
In steps (2) and (3) of Reaction Scheme DC, the nitro group of a substituted
quinoline of Formula XLV is first reduced to a 2-chloroquinohn-3,4-diamine of Formula
5 XLVI, which is then cyclized to a l#-imidazo[4,5-c]quinoline of Formula XLVTL Steps
(2) and (3) of Reaction Scheme IX can be carried out as described in steps (2) and (3) of
Reaction Scheme I.
In steps (4) and (5) of Reaction Scheme IX, a l#-imidazo[4,5-c]quinoline of
Formula XLVII is first aminated as described in step (5) of Reaction Scheme I to provide
10 a li/-imidazo[4,5-c]quinolin-4-amine of Formula XLVm, which is then reduced to a
6,7,8,9-tetrahydro-liy-imidazo[4,5-c]quinolin-4-amine of Formula XLIX according to the
method described in Reaction Scheme VI.
In step (6) of Reaction Scheme IX, the 4-amine of a 6,7,8,9-tetrahydro-l#-
imidazo[4,5-c]quinolin-4-amine of Formula XLIX is protected with suitable protecting
1 5 groups such as Boc groups. The protection reaction is conveniently carried out by
combining a tetrahydro-lJy-iinidazo[4,5-c]quinolin--4-amine of Formula XLIX with di-
tert-butyl dicarbonate in the presence of base, such as triethylamine, catalytic DMAP, or a
combination thereof The reaction can be carried out at room temperature in a suitable
solvent such as toluene. Other protecting groups can be installed in this step using known
20 synthetic methods.
In step (7) of Reaction Scheme IX, the hydroxy protecting group on a tetrahydro-
l#-imidazo[4,5-c]quinoline of Formula L is removed to reveal the hydroxy group in a
product of Formula LI. The deprotection reaction can be carried out using a variety of
conventional methods, depending on the protecting group used. When PG is a silyl group
25 such as tert-butyldimethylsilyl, the deprotection can be carried out by adding
tetrabutylammonium fluoride to a compound of Formula L in a suitable solvent such as
tetrahydrofuran (THF). The reaction can be carried out at a sub-ambient temperature, such
as -78 °C, and then warmed to room temperature.
Steps (8), (9), and (10) of Reaction Scheme IX can be carried out according to the
30 methods described above in steps (5), (6), and (7) of Reaction Scheme II to provide a
tetrahydro-l#-imidazo[4,5-c]quinoline of Formula LII, which is then deprotected to
provide a tetrahydro-li7-iiiiida2o[4,5-c]quinolin-4-amine of Formula IVb, a subgenus of
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Formulas I and IV. The removal of Boc protecting groups is conveniently carried out
under acidic conditions by adding hydrogen chloride in ethanol to a compound of Formula
LII in a suitable solvent such as ethanol. The reaction can be run at room temperature or
at an elevated temperature such as 60 °C.
5
Reaction Scheme DC
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For some embodiments, tetrahydronapthyridines of the invention can be prepared
according to Reaction Scheme X, wherein R f , X' c , R 2c , Ru, PG, and m are as defined
above. Steps (1) through (3) of Reaction Scheme X can be carried out according to the
methods described in steps (1) through (3) of Reaction Scheme IX, starting with a
[l,5]naphthyridine of Formula LIIL Some compounds of Formula Lin are known; others
can be prepared according to known methods. See, for example, International Publication
No. WO2005/018551.
In steps (4) and (5) of Reaction Scheme X, a l^-imidazo[4,5-c][l,5]naphthyridine
of Formula LV is first oxidized to a 5JV-oxide of Formula LVI, which is animated to yield
a l//-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula LVH. Steps (4) and (5) of
Reaction Scheme X can be carried out as described in steps (5) and (6) of Reaction
Scheme IV.
In step (6) of Reaction Scheme X, a l^-imidazo[4,5-c][l,5]naphthyridin-4-amine
of Formula LVH is reduced to a 6,7,8,94etrahydro-l^-imidazo[4,5-c][l,5]naphthyridin-4-
amine of Formula LVm, conveniently under the conditions described in Reaction Scheme
VI
Steps (7) through (12) of Reaction Scheme X can be carried out according to the
methods described in steps (6) through (1 1) of Reaction Scheme IX, respectively, to
provide a 6,7,8,9-tetrahydro-li7-imidazo[4,5-c][l,5]naphthyridin-4-amine of Formula
XXVIIb, a subgenus of Formulas I and IXa.
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For some embodiments, compounds of the invention can be prepared according to
5 Reaction Scheme XI, wherein R*, X, R 2 , and n are as defined above; PGi is a nitrogen
protecting group; Ri d is a subset of Ri that includes the rings:
or w , wherein R 1 is as defined above. In step (1) of Reaction Scheme
XI, an aldehyde of Formula LDC is converted to an aldoxime of Formula LX using
conventional methods. For example, an aldehyde of Formula LDC can be combined with
10 hydroxylamine hydrochloride in the presence of base such as triethylamine in a suitable
solvent such as dichloromethane. The reaction can be run at room temperature.
Aldehydes of Formula LIX can be prepared using conventional methods. For example,
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phthalimidoacetaldehyde diethyl acetal is a commercially available compound that can be
treated with acid to provide an aldehyde of Formula LDC
In step (2) of Reaction Scheme XI, an aldoxime of Formula LX is converted to an
a-chloroaldoxime of Formula LXI according to the method described in step (4) of
Reaction Scheme I. The a-chloroaldoxime of Formula LXI is converted in step (3) of
Reaction Scheme XI to an isoxazole or dihydroisoxazole-substituted compound of
Formula LXII by treatment with a base such as triethylamine to generate a nitrile oxide in
the presence of an alkene of formula R'-CH=CH 2 or an alkyne of formula R'-OC-H
according to the methods described in step (4) of Reaction Scheme I. Numerous alkenes
and alkynes of these formulas are commercially available; others can be prepared by
known methods.
In step (4) of Reaction Scheme XI, the protecting groups are removed from a
compound of Formula LXII to provide an amino-substituted isoxazole or dihydroisoxazole
for Formula LXm. The deprotection may be cairied out in a variety of ways depending
on the identity of the protecting group. For example, when a phthalimide protecting group
is used, the deprotection can be carried out by combining a compound of Formula LXII
with hydrazine or hydrazine hydrate in a suitable solvent such as ethanol or solvent
mixture such as ethanol/THF. The reaction can be carried out at room temperature or at an
elevated temperature such as the reflux temperature of the solvent.
In step (5) of Reaction Scheme XI, a 4-chloro-3-nitroquinoline of Formula LXIV is
combined with an amine of Formula LXIH according to the method described in step (1)
of Reaction Scheme I. In steps (6) and (7) of Reaction Scheme XI, the nitro group of a
substituted quinoline of Formula LXV is first reduced to a quinolin-3,4-diamine of
Formula LXVI, which is then cyclized to a l#-imidazo[4,5-c]quinoline of Formula
LXVTL Steps (6) and (7) of Reaction Scheme XI can be carried out as described in step
(3) of Reaction Scheme II and step (3) of Reaction Scheme I, respectively.
In steps (8) and (9) of Reaction Scheme XI, a li/-imidazo[4,5-c]quinoline of
Formula LXVII is first oxidized to a 5N-oxide of Formula LXVIII, which is aminated to
yield a li/-imidazo[4,5-c]quinolin-4-amine of Formula IHg, a subgenus of Formulas I and
HI. Steps (8) and (9) of Reaction Scheme XI can be carried out as described in steps (5)
and (6) of Reaction Scheme IV.
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Reaction Scheme XI
(Ra)n Rid
lllg
For some embodiments, compounds of the invention can be prepared according to
5 Reaction Scheme XII, wherein Ra, X', Ri a , R 2 , and n are as defined above. In step (1) of
Reaction Scheme XII, a 2,4-dichloro-3-nitroquinoline of Formula XV is combined with an
amine of Formula LXIIIa according to the method described in step (1) of Reaction
Scheme I. Amines of Formula LXIIIa can be prepared in two steps from a protected
amino-substituted alkene or protected amino-substituted alkyne. In the first step, the
10 alkene or alkyne group can be reacted with an a-chloroaldoxime of Formula XIX
according to the method described in step (4) of Reaction Scheme I, and the resulting
isoxazole or dihydroisoxazole is then deprotected to provide an amino of Formula LXIIIa.
Some protected amino-substituted alkenes and protected amino-substituted alkynes are
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commercially available, such as AH3-butynyl)phthalimide; others can be prepared by
known methods. Steps (2), (3), and (4) of Reaction Scheme XII can then be carried out
according to the methods described in step (3) of Reaction Scheme II, and step (3) and
step (5) of Reaction Scheme I, respectively, to provide a compound of Formula Hla.
Reaction Scheme XII
Synthetic transformations can be made at the R 2 position in many of the
compounds shown in Reaction Schemes I through X, if, for example, the carboxylic acid
or equivalent thereof used in step (3) of Reaction Scheme I, IX, or X, or step (4) of
Reaction Scheme II, IV, or Vm contains a protected hydroxy or amino group. Some acid
chlorides of this type are commercially available; others can be prepared by known
synthetic methods. A protected hydroxy or amino group thus installed at the R 2 position
can then be deprotected by a variety of methods well known to one of skill in the art. For
example, hydroxyalkylenyl group is conveniently introduced at the R 2 position by the
dealkylation of a methoxy- or ethoxyalkylenyl group, which can be installed by using a
methoxy- or ethoxy-substituted carboxylic acid equivalent, for example, methoxyacetyl
chloride, 2-methoxypropionyl chloride, or ethoxyacetyl chloride, in step (3) of Reaction
Scheme I or the analogous steps in the other Reaction Schemes. The dealkylation can be
carried out by treating a compound wherein R 2 is an alkoxyalkylenyl group with boron
tribromide in a suitable solvent such as dichloromethane at a sub-ambient temperature
such as 0 °C. Alternatively, acetoxyacetyl chloride can be used in step (3) of Reaction
Scheme I, and hydrolysis of the ester group to reveal a hydroxy group can be carried out
by conventional methods. The resulting hydroxy group may then be oxidized to an
aldehyde or carboxylic acid using conventional methods or converted to a leaving group
such as, for example, a chloro group using thionyl chloride or a trifluoromethanesulfonate
group using trifluoromethanesulfonic anhydride. The resulting leaving group can then be
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displaced by a variety of nucleophiles. Sodium azide can be used as the nucleophile to
install an azide group, which can then be reduced to an amino group using heterogeneous
hydrogenation conditions. An amino group at the R 2 position can be converted to an
amide, sulfonamide, sulfamide, or urea using conventional methods. A leaving group at
5 R 2 , such as a chloro or trifluoromethanesulfonate group, can also be displaced with a
secondary amine, a substituted phenol, or a mercaptan in the presence of a base such as
potassium carbonate, triethylamine, or tyiV-cttisopropylethylamine in a suitable solvent
such as 7V;A^dimethylacetamide (DMA) or DMF. For examples of these and other
methods used to install a variety of groups at the R 2 position, see U.S. Patent No.
10 5,389,640 (Gerster et al.). A hydroxyalkylenyl group at the R 2 position can also be
converted to a fluoroalkylenyl group' by treating a hydxoxy-substituted compound with
(diethylamino)sulfur trifluoride (DAST) in a suitable solvent such as dichloromethane at a
sub-ambient temperature, such as -78 °C. These synthetic transformations may
conveniently be carried out as the last steps in the synthesis.
15 Compounds of the invention can also be prepared using variations of the synthetic
routes shown in Reaction Schemes I through XI that would be apparent to one of skill in
the art. For example, the cycloaddition reaction described in step (4) of Reaction Scheme
I may be carried out on a compound of Formula XVI or Formula XXXIX so that the order
of steps in Reaction Schemes I and VHI is analogous to the order of steps in Reaction
20 Scheme IV. In another example, a 4-chloro-3-nitro[ 1 ,5]naphthyridine of Formula XXX
can be used instead of a 4-chloro-3-nitroquinoline of Formula LXIV in Reaction Scheme
XI to provide naphthyridine compounds of the invention. Compounds of the invention
can also be prepared using the synthetic routes described in the EXAMPLES below.
Prodrugs can be prepared in a variety of ways. For example, a compound wherein
25 R 2 is -X-OH (e.g. hydroxyalkyl) can be converted into a prodrug wherein R 2 is, for
example, -X-O-C^)^, -X-O-CO^-O-R,, or -X-O-CCR^-N^-R^ wherein X, R*,
and Rg are as defined above, using methods known to one skilled in the art. In addition, a
compound wherein R*> is hydroxy may also be converted to an ester, an ether, a carbonate,
or a carbamate. For any of these compounds containing an alcohol functional group, a
30 prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with
a group such as C^alkanoyloxymethyl, l-(Ci_ 6 alkanoyloxy) ethyl, l-methyl-l-(Ci. 6
alkanoyloxy)ethyl, Ci- 6 alkoxycarbonyloxymethyl, N-(Ci^ alkoxycarbonyl)aminomethyl,
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succinoyl, Ci- 6 alkanoyl, a-aminoC M alkanoyl, arylacyl, -P(0)(OH) 2 , -P(0)(0-Ci-6 alkyl) 2 ,
C^alkoxycarbonyl, C\-e alkylcarbamoyl, and a-aminoacyl or a-aminoacyl-a-aminoacyl,
where each a-aminoacyl group is independently selected from racemic, D, and L-amino
acids. For compounds containing an alcohol functional group, particularly useful prodrugs
5 are esters made from carboxylic acids containing one to six carbon atoms, unsubstituted or
substituted benzoic acid esters, or esters made from naturally occurring L-amino acids.
Prodrugs can also be made from a compound containing an amino group by
conversion of the amino group to a functional group such as an amide, carbamate, urea,
amidine, or another hydroylizable group using conventional methods. A prodrug of this
10 type can be made by the replacement of a hydrogen atom in an amino group, particularly
the amino group at the 4-position, with a group such as -C(0)-R', a-aminoacyl,
a-aminoacyl-a-aminoacyl, -C(0)-0-R', -C(0)-N(R")-R\, -C(=NY , )-R I ,
-CH(OH)-C(0)-OY', -CH(OC M alkyl)Yo, -CH 2 Y h or -CH(CH 3 )Y i; wherein R' and R" are
each independently C M0 alkyl, C3-7 cycloalkyl, or benzyl, each of which may be
15 unsubstituted or substituted by one or more substituents selected from the group consisting
of halogen, hydroxy, nitro, cyano, carboxy, Ci- 6 alkyl, C1-4 alkoxy, aryl, heteroaryl,
arylCi.4 alkylenyl, heteroarylC M alkylenyl, haloC M alkylenyl, haloC M alkoxy,
-0-C(0)-CH 3 , -C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 ,
with the proviso that R" may also be hydrogen; each a-aminoacyl group is independently
20 selected from racemic, D, or L-amino acids; Y* is hydrogen, Ci- 6 alkyl, or benzyl; Y 0 is
Ci-6 alkyl, carboxyCi.6 alkylenyl, aminoCi-4 alkylenyl,
mono-N-Ci-6 alkylaminoCi-4 alkylenyl, or di-N,N-C\. 6 alkylaminoCi-4 alkylenyl; and Yi is
mono-A^Ci. 6 alkylamino, di-N t N-C x ^ alkylamino, moipholin-4-yl, piperidin-l-yl,
pyrrohdin-l-yl, or 4-Cm alkylpiperazin-l-yl. For compounds containing an amine
25 functional group, particularly useful prodrugs are amides derived from carboxylic acids
containing one to ten carbon atoms, amides derived from amino acids, and carbamates
containing one to ten carbon atoms.
Pharmaceutical Compositions and Biological Activity
30 Pharmaceutical compositions of the invention contain a therapeutically effective
amount of a compound or salt of the invention as described above in combination with a
pharmaceutically acceptable carrier.
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The terms "a therapeutically effective amount" and "effective amount" mean an
amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect,
such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral
activity. Although the exact amount of active compound or salt used in a pharmaceutical
5 composition of the invention will vary according to factors known to those of skill in the
art, such as the physical and chemical nature of the compound or salt, the nature of the
carrier, and the intended dosing regimen, it is anticipated that the compositions of the
invention will contain sufficient active ingredient to provide a dose of about 100
nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably
1 0 about 1 0 micrograms per kilogram (ng/kg) to about 5 mg/kg, of the compound or salt to
the subject. A variety of dosage forms may be used, such as tablets, lozenges, capsules,
parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal
patches, transmucosal patches and the like.
The compounds or salts of the invention can be administered as the single
1 5 therapeutic agent in the treatment regimen, or the compounds or salts of the invention may
be administered in combination with one another or with other active agents, including
additional immune response modifiers, antivirals, antibiotics, antibodies, proteins,
peptides, oligonucleotides, etc.
Compounds or salts of the invention have been shown to induce the production of
20 certain cytokines in experiments performed according to the test set forth below. These
results indicate that the compounds or salts are useful as immune response modifiers that
can modulate the immune response in a number of different ways, rendering them useful
in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds
25 or salts of the invention generally include interferon-a (IFN-a) and/or tumor necrosis
factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may
be induced by compounds or salts of the invention include IFN-a, TNF-a, IL-1, EL-6, IL-
10 and EL- 12, and a variety of other cytokines. Among other effects, these and other
cytokines can inhibit virus production and tumor cell growth, making the compounds or
30 salts useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the
invention provides a method of inducing cytokine biosynthesis in an animal comprising '
administering an effective amount of a compound or salt or composition of the invention
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to the animal. The animal to which the compound or salt or composition is administered
for induction of cytokine biosynthesis may have a disease as described infra, for example
a viral disease or a neoplastic disease, and administration of the compound or salt may
provide therapeutic treatment. Alternatively, the compound or salt may be administered to
5 the animal prior to the animal acquiring the disease so that administration of the
compound or salt may provide a prophylactic treatment.
In addition to the ability to induce the production of cytokines, compounds or salts
of the invention can affect other aspects of the innate immune response. For example,
natural killer cell activity may be stimulated, an effect that may be due to cytokine
10 induction. The compounds or salts may also activate macrophages, which in turn
stimulate secretion of nitric oxide and the production of additional cytokines. Further, the
compounds or salts may cause proliferation and differentiation of B-lymphocytes.
Compounds or salts of the invention can also have an effect on the acquired
immune response. For example, the production of the T helper type 1 (T H 1) cytokine IFN-
1 5 y may be induced indirectly and the production of the T helper type 2 (T H 2) cytokines IL-
4, DL-5 and EL- 13 may be inhibited upon administration of the compounds or salts.
Whether for prophylaxis or therapeutic treatment of a disease, and whether for
effecting innate or acquired immunity, the compound or salt or composition may be
administered alone or in combination with one or more active components as in, for
20 example, a vaccine adjuvant. When administered with other components, the compound
or salt and other component or components may be administered separately; together but
independently such as in a solution; or together and associated with one another such as
(a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
Conditions for which compounds or salts identified herein may be used as
25 treatments include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection by an
adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an
orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus
30 (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus
(RSV)), a coronavirus (e.g., SARS), apapovavirus (e.g., papillomaviruses, such as those
that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B
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virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
lentivirus such as HIV);
(b) bacterial diseases such as, for example, diseases resulting from infection by
bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus,
5 Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,
Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus,
Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia,
Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such chlamydia, fungal diseases including but not
10 limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic
diseases including but not limited to malaria, Pneumocystis carnii pneumonia,
leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
(d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia,
actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma,
1 5 Kaposi's sarcoma, melanoma, leukemias including but not limited to myelogeous
leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;
(e) T H 2-mediated, atopic diseases, such as atopic dermatitis or eczema,
eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
20 (f) certain autoimmune diseases such as systemic lupus erythematosus, essential
thrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and
(g) diseases associated with wound repair such as, for example, inhibition of keloid
formation and other types of scarring (e.g., enhancing wound healing, including chronic
wounds).
25 Additionally, a compound or salt of the present invention may be useful as a
vaccine adjuvant for use in conjunction with any material that raises either humoral and/or
cell mediated immune response, such as, for example, live viral, bacterial, or parasitic
immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or
bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;
30 glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines;
recombinant proteins; and the like, for use in connection with, for example, BCG, cholera,
plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B,
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parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria,
hemophilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines,
adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague,
HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus,
5 rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.
Compounds or salts of the present invention may be particularly helpful in
individuals having compromised immune function. For example, compounds or salts may
be used for treating the opportunistic infections and tumors that occur after suppression of
cell mediated immunity in, for example, transplant patients, cancer patients and HIV
10 patients.
Thus, one or more of the above diseases or types of diseases, for example, a viral
disease or a neoplastic disease may be treated in an animal in need thereof (having the
disease) by administering a therapeutically effective amount of a compound or salt of the
invention to the animal.
15 An amount of a compound or salt effective to induce cytokine biosynthesis is an amount
sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells
and B-cells to produce an amount of one or more cytokines such as, for example, IFN-a,
TNF-a, IL-1, IL-6, IL-10 and EL- 12 that is increased (induced) over a background level of
such cytokines. The precise amount will vary according to factors known in the art but is
20 expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ng/kg to
about 5 mg/kg. The invention also provides a method of treating a viral infection in an
animal and a method of treating a neoplastic disease in an animal comprising
administering an effective amount of a compound or salt or composition of the invention
to the animal. An amount effective to treat or inhibit a viral infection is an amount that
25 will cause a reduction in one or more of the manifestations of viral infection, such as viral
lesions, viral load, rate of virus production, and mortality as compared to untreated control
animals. The precise amount that is effective for such treatment will vary according to
factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 jig/kg to about 5 mg/kg. An amount of a compound or salt effective
30 to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in
the number of tumor foci. Again, the precise amount will vary according to factors
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known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 fig/kg to about 5 mg/kg.
In addition to the formulations and uses described specifically herein, other
formulations, uses, and administration devices suitable for compounds of the present
5 invention are described in, for example, International Publication Nos. WO 03/077944 and
WO 02/036592, U.S. Patent No. 6,245,776, and U.S. Publication Nos. 2003/0139364,
2003/185835, 2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.
1 0 Objects and advantages of this invention are further illustrated by the following
examples, but the particular materials and amounts thereof recited in these examples, as well
as other conditions and details, should not be construed to unduly limit this invention.
EXAMPLES
15
Example 1
2-(Ethoxymethyl)-l -[(3-me
c]quinolin-4-amine
20 Part A
Triethylamine (17.0 mL, 123 mmol) was added to a 0 °C solution of 2,4-dichloro-
3-nitroquinoline (20.0 g, 82.3 mmol) in dichloromethane (350 mL) followed by the
dropwise addition of allylamine (5.90 mL, 78.2 mmol). The solution was allowed to stir
and warm to room temperature overnight. The solvent was evaporated under reduced
25 pressure and the resulting orange solid was suspended in water (300 mL). Solid sodium
carbonate was added to adjust the pH to 10-1 1 and the suspension was stirred for 2 hours
at 0 °C. A yellow solid was isolated by filtration and dried under vacuum overnight to
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yield iV-allyl-2-chloro-3-nitroquinolin-4-aniine (21 .7 g) that contained small amounts of an
impurity and water.
PartB
An aqueous solution (200 mL) of potassium carbonate (55.3 g, 400 mmol) and
5 sodium dithionate (62.7 g, 360 mmol) was added dropwise over 30 minutes to a mixture of
AT-allyl-2-chloro-3-nitroquinolin-4-amine (21.0 g, 79.9 mmol) and ethyl viologen
dibromide (1.80 g, 4.80 mmol) in dichloromethane (320 mL) and water (40 mL) under a
nitrogen atmosphere. The dark blue-green mixture was stirred rapidly and was heated at
reflux overnight. The mixture was transferred to a separator/ funnel and the layers were
10 separated. The aqueous layer was extracted with dichloromethane. The combined organic
layers were filtered through CELITE filter agent, dried over magnesium sulfate, filtered,
and concentrated to a dark oil. The crude product was purified by suction filter
chromatography (silica gel, gradient elution from 3:1 to 1:3 hexanes/ethyl acetate, then 4:1
dichloromethane/ethyl acetate) to afford pure product Af*-allyl-2-chloroquinoline-3, 4-
15 diamine (12.06 g) along with some impure product (3.10 g).
PartC
Ethoxyacetyl chloride (8.80 g, 71.8 mmol) was added dropwise to a solution of 7V 4 -
allyl-2-chIoroquinoline-3,4-diamine (15.2 g, 65.3 mmol) in acetonitrile (300 mL) at room
temperature. After 45 minutes, the reaction mixture was filtered and an orange solid
20 (approximately 17 g) was isolated. The solid was dissolved in a solution of ethanol (240
mL) and water (80 mL). Sodium hydroxide (3.92 g, 98.0 mmol) was added and the
solution was heated at reflux for 2 hours. The ethanol was removed under reduced
pressure and the remaining aqueous solution was extracted several times with
dichloromethane. The combined organic layers were dried over magnesium sulfate,
25 filtered, and concentrated to an orange solid. The solid was triturated with ethyl acetate
and isolated by filtration to yield 6 g of a pale yellow solid. The filtrate was concentrated
and purified by suction filter chromatography (silica gel with 97:3
dichloromethane/methanol as the eluent) to yield an additional 5 g of product. The
material was combined to provide 11 g of l-allyl^-chloro^^ethoxymethyl)-!/^
30 imidazo[4,5-c]quinoline.
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PartD
To a 0 °C solution of acetaldehyde oxime (1.22 mL, 20.0 mmol) in N,N-
dimethylformamide (DMF, 20 mL) was added N-chlorosuccinimide (2.67 g, 20.0 mmol)
over a period of 1 0 minutes. After 15 minutes, the solution was wanned to 50 °C for 1
hour. After cooling to room temperature, the solution was partitioned between ice water
and ethyl acetate. The aqueous layer was extracted with two additional portions of ethyl
acetate. The combined organic layers were washed with water and brine, dried over
magnesium sulfate, filtered, and concentrated to provide N-hydroxyethanimidoyl chloride
as a pale yellow oil.
PartE
Triethylamine (1.04 mL, 7.46 mmol) was added to a 0 °C solution of l-allyl-4-
chloro-2-(ethoxymethyl)-lJ7-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-
hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The
reaction solution was allowed to warm slowly to room temperature and stir overnight
under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated
aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and
concentrated. The crude product was purified by flash chromatography (silica gel, elution
with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-l-[(3-methyl-
4,5-dihydroisoxazol-5-yl)m^ (1.34 g) as a white solid.
PartF
4-Chloro-2-(ethoxymethyl)-l
imidazo[4,5-c]quinoline (1.30 g, 3.62 mmol) was treated with a solution of 7 M ammonia
in methanol (60 mL), and the mixture was sealed in a pressure vessel and heated at 150 °C
for 24 hours. The volatiles were removed under reduced pressure, and the residue was
partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The
aqueous layer was extracted with two additional portions of dichloromethane. The
combined organic layers were washed with brine, dried over magnesium sulfate, filtered,
and concentrated. The crude product was purified by flash chromatography (silica gel,
gradient elution using 98:2 to 96:4 dichloromethane/methanol) to afford 2-(ethoxymethyl)-
1 -[(3-methyl-4,5-dihydroisoxa^
g) as a white solid that was crystallized from acetonitrile to provide white needles, mp
204-205 °C.
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*H NMR (300 MHz, CDC1 3 ) 5 7.90 (dd, J= 8.2, 0.8 Hz, 1H), 7.83 (dd, J~ 8.4, 0.9 Hz,
1H), 7.53 (dt, 7= 7.1, 1.3 Hz, 1H), 7.32 (dt, J= 8.2, 1.2 Hz, 1H), 5.46 (br s, 2H), 5.14 (m,
1H), 4.96 (d, /= 12.7 Hz, 1H), 4.88 (dd, J= 15.4, 7.7 Hz, 1H), 4.81 (d, 12.7 Hz, 1H),
4.72 (dd, J = 15.4, 4.4 Hz, 1H), 3.62 (q, ./= 7.0 Hz, 2H), 3.12 (dd, J= 16.9, 10.6 Hz, 1H),
2.86 (dd, J= 17.2, 6.5 Hz, 1H), 2.01 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H);
MS (APCI) m/z 340 (M + H 4 );
Anal, calcd for C18H21N5O2: C, 63.70; H, 6.24; N, 20.63. Found: C, 63.44; H, 6.15; N,
21.00.
Example 2
2-(Ethoxymethyl)- 1 -[(3-phenyl-4,5-dihydroisoxazo^
c]quinolin-4-amine
Part A
AT-Hydroxybenzenecarboximidoyl chloride (13.7 g) was prepared according to the
method described in Part D of Example 1 by reacting benzaldehyde oxime (1 1 .5 g, 94.9
mmol) in DMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol) and was obtained
as a white solid. Triethylamine (0.69 mL, 4.97 mmol) was added to a solution of N-
hydroxybenzenecarboximidoyl chloride (644 mg, 4.14 mmol) and l-allyl-4-chloro-2-
(ethoxymethyl)-l J f/-imidazo[4,5-c]quinohne (prepared as described in Part C of Example
1, 1.00 g, 3.32 mmol) in dichloromethane (50 mL) at room temperature. The solution was
stirred overnight and then was washed with saturated aqueous sodium bicarbonate, dried
over magnesium sulfate, filtered, and concentrated. The crude product was purified by
flash chromatography on silica gel to afford 4-chloro-2-(ethoxymethyl)-l-[(3-phenyl-4,5-
dihydroisoxazol-5-yl)methyl]-l/7-imidazo[4,5-c]quinoline as a pale yellow solid (1.19 g).
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PartB
4-Cmoro-2Kethoxymethyl)-l-[(3-phenyM J 5Kiihydroisoxazol-5-yl)methyl]-l/f-
imidazo[4,5-c]quinoline (1.50 g, 3.56 mmol) was treated with a solution of 7 M ammonia
in methanol (30 mL) at 140 °C for 15 hours according to the method described in Part F of
Example 1 . Chloroform was used in the work-up procedure instead of dichloromethane.
The crude product was purified by flash chromatography (silica gel, elution with 97:3
dichloromethane/methanol) to afford 2-(ethoxymethyl)-l-[(3-phenyl-4 J 5-dihydroisoxazol-
5-yl)memyl]-l/f-imidazo[4,5-c]quinolin-4-amine (1.17 g) as a yellow solid.
Recrystallization afforded white needles, mp 235-237 °C.
! H NMR (300 MHz, CDC1 3 ) 5 7.97 (dd, J= 8.2, 0.9 Hz, 1H), 7.84 (dd, J= 8.4, 1.0 Hz,
1H), 7.67-7.64 (m, 2H), 7.53 (ddd,/= 8.4, 7.1, 1.3 Hz, 1H), 7.46-7.38 (m, 3H), 7.31 (ddd,
J= 8.2, 7.1, 1.3 Hz, 1H), 5.41 (br s, 2H), 5.37-5.34 (m, 1H), 5.02-4.77 (m, 4H), 3.59 (q, /
- 7.0 Hz, 2H), 3.53 (m, 1H), 3.34 (dd, J= 16.8, 6.3 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H);
MS (APCI) m/z 402 (M + it);
Anal, calcd for Cjs^NsOz: C, 68.81; H, 5.77; N, 17.44. Found: C, 68.71; H, 5.91; N,
17.44.
Example 3
2-(Ethoxymemyl)-l-[(3-phenylisoxazol-5-yl)memyI]-l^mndazo[4,5-c]qumolin-4-amine
Part A
Propargylamine (25 mL, 0.36 mol) was added dropwise over a period of five
minutes to a 4.5 °C solution of 2,4-dichloro-3-nitroquinoline (84.4 g, 0.347 mol) and
triethylamine (73 mL, 0.52 mol) in dichloromethane (1.2 L). After one hour, the solution
was allowed to warm to room temperature. After several days, the solvent was evaporated
under reduced pressure and the resulting solid was triturated with water and isolated by
filtration. The solid was rinsed with water and toluene (500 mL), then was dissolved in
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dichloromethane and toluene and concentrated under reduced pressure to remove residual
water. The solid was dissolved in methanol and ether and concentrated under reduced
pressure to afford 2-chloro-3-nitro-iV L prop-2-ynylquinoIin-4-amine as yellow-brown solid
(79.5 g) that contained some impurities and was used without further manipulation.
PartB
An aqueous solution (1.5 L) of sodium dithionate (265 g, 1.52 mol) was added to a
solution of 2-cMoro-3-nitro-AT-prop-2-ynylquinolin-4-amine (79.3 g, 0.303 mol) in ethanol
(750 mL) and acetonitrile (950 mL). A fine white precipitate formed within seconds. The
reaction was worked-up after thin layer chromatography (TLC) analysis of the reaction
mixture indicated that the reaction was complete. The solids were removed by filtration
and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under
reduced pressure to remove the volatiles, leaving an aqueous solution that was extracted
with several portions of dichloromethane. The organic layers were combined, washed
with brine, dried over magnesium sulfate, filtered, and concentrated to yield 2-chloro-iV 4 -
prop-2-ynylquinoline-3,4-diamine (43.5 g) that was approximately 60% pure and was used
without further purification.
PartC
Ethoxyacetyl chloride (89%, 28 g, 0.20 mol) was added dropwise to a solution of
2-chloro-7^-prop-2-ynylquinoline-3,4-diamine (43.5 g, 0.188 mol) and triethylamine (39
mL, 0.28 mol) in dichloromethane (600 mL) at 6 °C. After two hours, the reaction
mixture was diluted with dichloromethane and washed with saturated aqueous sodium
bicarbonate. The aqueous layer was back-extracted with dichloromethane three times.
The organic layers were combined and washed twice with water and brine, dried over
magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting
brown solid was triturated with toluene with heating. A fine tan solid was isolated by
filtration, rinsed with diethyl ether, and dried to yield N-[2-chloro-4-(prop-2-
ynylamino)quinolin-3-yl]-2-ethoxyacetamide (47.2 g).
PartD
A solution ofA^[2-chloro-4-(prop-2-ynylamino)quinolin-3-yl]-2-ethoxyacetamide
(26.7 g, 84.0 mmol) and triethylamine (17.5 mL, 126 mmol) in ethanol (250 mL) was
heated at 60 °C for 1.7 days. Additional triethylamine (17.5 mL) was added and the
solution was heated at 60 °C for two more days. The volatiles were removed under
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reduced pressure and the resulting white solid was triturated with water, isolated by
filtration, and dried to provide 4-chloro-2-(ethoxyme%l)4-prop-2-ynyl-l^-imidazo[4,5-
c]quinoline (24.2 g, 96%).
PartE
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of
Example 2, L72 g, 10.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl>l-
prop-2-ynyl-li/-imidazo[4,5-c]quinoline (3.00 g, 10.0 mmol) and triethylamine (1.70 mL,
12.0 mmol) in dichloromethane (40 mL). The solution was heated at reflux under a
nitrogen atmosphere for 3.5 hours and additional Af-hydroxybenzenecarboximidoyl
chloride (0. 1 g) was added. The solution was heated at reflux for one hour more, then was
allowed to cool to room temperature and was diluted with dichloromethane. The solution
was transferred to a separatory funnel and was washed with water and brine, dried over
sodium sulfate, filtered, and concentrated. The crude product was purified by flash
chromatography (silica gel, gradient elution from 4:1 to 3:2 hexanes/ethyl acetate) to
provide pure 4-chloro-2-(ethoxymethyl)-l-[(3-phenylisoxazol~5-yl)methyl]-l//-
imidazo[4,5-c]quinoline (1.48 g).
PartF
4-CMoro-2<ethoxymethyl)-l-[(3-phenyH^
c]quinoline (1.48 g, 3.53 mmol) was treated with a solution of 7 M ammonia in methanol
(25 mL) at 150 °C for 17 hours. The volatiles were removed under reduced pressure and
the resulting oil was diluted with dichloromethane and 1 M hydrochloric acid. A white
solid formed and 50% aqueous sodium hydroxide was added to dissolve the solid. The
aqueous layer was separated and extracted with dichloromethane. The organic layers were
combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to
an oil. Upon treatment of the oil with diethyl ether, a solid formed. The solid was purified
by flash chromatography (silica gel, eluting with a mixture of 95% dichloromethane and
5% of a solution of 80% chloroform, 18% methanol, and 2% NH4OH (CMA)) followed by
several recrystallizations from acetonitrile to provide 2-(ethoxymethyl)-l-[(3-
phenylisoxazol-5-yl)methyl]-li/-imidazo[4,5-c]quinohn-4-amine (0.505 g) as a white
powder, mp 215.0-216.0 °C.
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J H NMR (300 MHz, DMSO-rf tf ) 8 7.98 (d, J= 7.6 Hz, 1H), 7.79 (m, 2H), 7.61 (d, /= 7.5
Hz, 1H), 7.38-7.43 (m, 4H), 7.17 (t, 7.5, 1H), 6.85 (s, 1H), 6.69 (s, 2H), 6.15 (s, 2H),
4.88 (s, 2H), 3.50 (q, J= 6.9, 2H), 0.99 (t, 7= 6.9 Hz, 3H);
MS (APCI) /72/z 400 (M + H) + ;
Anal, calcd for C23H21N5O2: C, 69.16; H, 5.30; N, 17.53. Found: C, 69.29; H, 5.22; N,
17.65.
Example 4
2-(Ethoxymethyl)- 1 -[(3-methylisoxazol-5-yl)methyl]- l#-imidazo[4,5-c]quinolin-4-amine
NhL
A^Hydroxyethanimidoyl chloride (prepared as described in Part D of Example 1,
2.10 g, 22.5 mmol) was added to a solution of 4-cMoro-2-(ethoxymethyl)-l-prop-2-ynyl-
li/-imidazo[4,5-c]quinoline (prepared as described in Part D of Example 3, 5.39 g, 18.0
mmol) and triethylamine (3.70 mL, 27.0 mmol) in dichloromethane (60 mL). The solution
was heated at reflux for 16 hours and then was concentrated under reduced pressure. The
crude product was purified by flash chromatography (silica gel, gradient elution from 7:3
to 2:3 hexanes/ethyl acetate) to provide 4-chloro-2-(ethoxymethyl)-l-[(3-methylisoxazol-
5-yl)methyl]-l//-imidazo[4,5-c]quinoline (4.21 g) as a white solid.
A slurry of 4-cUoro-2-(ethoxymethyl)-l-[(3-methylisoxazol-5-yl)methyl]--l//-
imidazo[4,5-c]quinoline (4.21 g, 1 1.8 mmol) in a solution of 7 M ammonia in methanol
(50 mL) was heated at 1 50 °C for 22 hours in a Parr pressure vessel. The volatiles were
removed under reduced pressure and the resulting solid was triturated with water. A tan
solid was isolated and purified by flash chromatography (silica gel, gradient elution from
9:1 to 1 :1 chloroform/CMA) to yield 43.2 mg of pure 2-(ethoxymethyl)-l-[(3-
methylisoxazol-5-yl)methyl]-lJ^-imidazo[4,5-c]quinolin-4-amine as a white powder, mp
178.0-180.0 °C.
Part A
PartB
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] H NMR (300 MHz, DMSO-J*) 5 7.93 (d, 7.5 Hz, 1H), 7.60 (d, J= 7.5 Hz, 1H), 7.41
(t, J = 7.1 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 6.69 (s, 2H), 6.10 (s, 1H), 6.04 (s, 2H), 4.83
(s, 2H), 3.48 (q, 7.0 Hz, 2H), 2.1 1 (s, 3 H), 1.05 (t, J = 7.0, 3H);
MS (APCI) tk/z 338 (M + H) + ;
Anal, calcd for C18H19N5O2: C, 64.08; H, 5.68; N, 20.76. Found: C, 63.74; H, 5.43; N,
20.42.
Example 5
2-(Ethoxyme%l)4^(3-pyri^
amine
Part A
3-Pyridinecarboxaldehyde oxime was prepared by treating 3-
pyridinecarboxaldehyde (10 mL, 106 mmol) with hydroxylamine hydrochloride (8.10 g,
117 mmol) and 50% aqueous sodium hydroxide (2 mL) in ethanol (100 mL) and water
(200 mL) for 17 hours. The solution was adjusted to pH 14 with the addition of 50%
(w/w) aqueous sodium hydroxide. The solution was extracted with several portions of
dichloromethane. The combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and concentrated under reduced pressure to yield 8.3 g of a
white solid. The aqueous layers were combined and back-extracted with chloroform (5 x
1 L) to yield additional product. The total amount of 3-pyridinecarboxaldehyde oxime
obtained was 12.24 g.
PartB
Af-Chlorosuccinimide (1.09 g, 8.19 mmol) was added to a 6 °C solution of 3-
pyridinecarboxaldehyde oxime (1 .00 g, 8. 1 9 mmol ) in tetrahydofiiran (THF) (25 mL).
The solution was heated at 50 °C for 2 h. 4-Chloro-2-(ethoxymethyl).l-prop-2-ynyl-l//.
imidazo[4,5-c]quinoline (prepared as described in Part D of Example 3, 1.96 g, 6.55
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mmol) and triethylamine (1.70 mL, 12.3 mmol) were added to the reaction, which was
heated at 50 °C for 17 hours. The volatiles were removed under reduced pressure and the
residue was partitioned between dichloromethane and saturated aqueous potassium
carbonate. The aqueous layer was extracted multiple times with dichloromethane and
chloroform. The organic layers were combined, dried over sodium sulfate, filtered, and
concentrated. The crude product was purified by flash chromatography (silica gel,
gradient elution with 1:1 to 1:4 hexanes/ethyl acetate) to yield 4-chloro-2-(ethoxymethyl)-
l-[(3-pyridin-3-ylisoxazol-5-yl)metfy^ (1 52 g ^
PartC
A slurry of 4-chloro-2-(ethoxymethyl)-l -[(3-pyridin-3-ylisoxazol-5-yl)methyl]-
l#-imidazo[4,5-c]quinoline (1.52 g, 3.62 mmol) in a solution of 7 M ammonia in
methanol (15 mL) was heated at 150 °C for 20 hours in a Parr pressure vessel. The
volatiles were removed under reduced pressure and the resulting residue was partitioned
between dichloromethane and 1 M aqueous sodium hydroxide. The aqueous layer was
extracted with several portions of dichloromethane. The organic phases were combined,
washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography (silica gel, gradient
elution 10% to 30% CMA/chloroform) to yield 2-(ethoxymethyl)-l-[(3-pyridin-3-
ylisoxazol-5-yl)me%l]-li?-imidazo[4,5-c]quinohn--4--amine (653 mg, 45%) as white
powder that was dried under vacuum at 70 °C, mp 240.0-242.0 °C. *H NMR (300 MHz,
DMSO-4058.99 (d,J=1.7Hz, 1H), 8.64 (dd, ,7=3.2, 1.6Hz, 1H), 8.16-8.20 (m, 1H),
7.97 (d, J= 7.5 Hz, 1H), 7.61 (d, J= 7.4 Hz, 1H), 7.41-7.50 (m, 2H), 7.17 (t, J= 7.0 Hz,
1H), 6.97 (s, 1H), 6.17 (s, 2H), 5.75 (s, 2H), 4.88 (s, 2H), 3.50 (q, J= 7.0 Hz, 2H), 0.98 (t,
J =7.0, 3H);
MS (APCI) in/z 401 (M + H) + ;
Anal, calcd for C22H20N6CVO.ICH2CI2: C, 64.91; H, 4.98; N, 20.55. Found: C, 64.70; H,
4.95; N, 20.70.
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Example 6
2-(Ethoxymethyl)-l-[3-(3-pyridin-3-yfo
amine
NH 2
5 Part A
/?-Toluenesulfonyl chloride (21.4 g, 1 12 mmol) was added slowly to a stirred
solution of 4-pentyn-l-ol (1 1.5 mL, 124 mL) and triethylamine (17.2 mL, 124 mmol) in
dichloromethane (100 mL) at room temperature. After 22 hours, the solution was diluted
with dichloromethane, washed with water, dried over sodium sulfate, filtered, and
10 concentrated. The crude product was purified by flash chromatography (silica gel,
gradient elution from 95:5 to 85:15 hexanes/ethyl acetate) to afford the product pent-4-
ynyl 4-methylbenzenesulfonate (23.4 g, 87%) as a colorless oil.
PartB
A mixture of pent-4-ynyl 4-methylbenzenesulfonate (23.4 g, 98.2 mmol) and
15 sodium azide (16.6 g, 255 mmol) in DMF (80 mL) was heated at 60 °C for 3.5 hours. The
reaction was allowed to cool to room temperature and water was added until the remaining
sodium azide dissolved. The solution was extracted with several portions of diethyl ether.
The combined organic layers were washed with water, dried over magnesium sulfate,
filtered, and concentrated to an oil. The oil was dissolved in diethyl ether (80 mL) and
20 cooled to 0 °C. Triphenylphosphine (25.8 g, 98.2 mmol) was added and gas evolution was
observed. After 19 hours, water (10 mL) and tetrahydrofuran (50 mL) were added and the
mixture was stirred for 20 hours at room temperature. The mixture was partitioned
between 1 M hydrochloric acid (400 mL) and dichloromethane (400 mL). The aqueous
phase was washed with dichloromethane. The aqueous phase was concentrated under
25 reduced pressure to a white solid that was crystallized from ethanol/water to yield pent-4-
yn-l-amine hydrochloride as a white powder (8.15 g).
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PartC
Pent-4-yn-l-amine hydrochloride (5.48 g, 45.8 mmol) was added to a 6 °C solution
of 2,4-dichloro-3-nitroquinoline (10.6 g, 43.6 mmol) and triethylamine (15.2 mL, 109
mmol) in dichloromethane (100 mL). After 30 minutes, the solution was allowed to warm
to room temperature. After 5 hours, the volatiles were removed under reduced pressure
and the solid residue was triturated with water and isolated by filtration. The filter cake
was rinsed with water and toluene and was allowed to dry for several days to yield 2-
cUoro-3-mtro-A^-pent-4-ynylquinohn-4-amine as an orange solid (13.16 g).
PartD
An aqueous solution (125 mL) of sodium dithionate (38.0 g, 218 mmol) was added
to a solution of 2-chloro-3-nitro-A r -pent-4-ynylqxiinolin-4-amine (12.64 g, 43.63 mmol) in
ethanol (15 mL) and acetonitrile (130 mL). A fine white precipitate formed within
seconds. After 2.5 hours, the volatiles were removed under reduced pressure leaving a
yellow aqueous mixture that was diluted with water (1 L) and washed with
dichloromethane (250 mL x 3). The organic layers were combined, washed with water
and brine, dried over magnesium sulfate, filtered, arid concentrated to yield 2-chloro-TV 4 -
pent-4-ynylquinoline-3,4-diamine as an amber oil (8.10 g) that was used without further
purification.
PartE
Ethoxyacetyl chloride (96%, 4.40 g, 34.3 mmol) was added to a 6 °C solution of 2-
cWoro-A^-pent-4-ynylquinoUne-3,4-diamine (8.10 g, 31.2 mmol) and triethylamine (6.50
mL, 46.8 mmol) in dichloromethane (100 mL). Additional ethoxyacetyl chloride (3.0 g)
was added after 45 minutes until all the starting material had been consumed. The
solution was diluted with dichloromethane and washed with saturated aqueous potassium
carbonate, water, and brine, dried over potassium carbonate, filtered, and concentrated to
afford i\^[2-cUoro-4-(pent-4-ynylamino)quinolin-3-yl]-2-ethoxyacetaim as a pale
yellow solid (10.23 g).
PartF
A solution ofiV-[2-chloro-4-(pent^-ynylamino)qtunolin-3-yl]-2-ethoxyacetamide
(10.23 g, 29.58 mmol) and 6 M aqueous potassium carbonate (7.40 mL, 44.4 mmol) in 9:1
ethanol/water (100 mL) was heated at 50°C for 16 hours. The volatiles were removed
under reduced pressure and the resulting slurry was partitioned between ethyl acetate and
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water. The organic phase was washed with water (2 x) and brine (2 x), dried over
magnesium sulfate, filtered, and concentrated to afford 4-chloro-2-(ethoxymethyl)-l-pent-
4-ynyl-l#-inudazo[4,5-c]qumoline as a slightly impure tan solid (9.5 g).
PartG
4-Chloro-2-(emoxyme%l)-l-pent-4-ynyl-li/-imidazo[4,5-c]quinoline(3.65 g,
11.1 mmol) was converted to 4-chloro-2-(emoxyme%l)-l-[3-(3-pyridin-3-yUsoxazol-5-
yl)propyl]-liy-imidazo[4,5-c]quinoline (1.78 g, 36%) following the method described in
Parts A and B of Example 5.
PartH
Aslurryof4-chloro-2<emoxymemyl)-l-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-
l#-imidazo[4,5-c]qwnoline (1.78 g, 3.97 mmol) in a solution of 7 M ammonia in
methanol (20 mL) was heated at 150 °C for 20 hours in a Parr pressure vessel. The
volatiles were removed under reduced pressure and the resulting oil was partitioned
between dichloromethane and 1 M KOH. The aqueous layer was extracted with
dichloromethane. The organic layers were combined, washed with water and brine, dried
over magnesium sulfate, filtered, and concentrated. The crude product was purified by
flash chromatography (silica gel, gradient elution from 9:1 to 4:1 chloroform/CMA).
After concentration of the appropriate fractions, a white solid was obtained. The white
solid was triturated with diethyl ether and dried at 80 °C under vacuum to provide 2-
(ethoxymemyl)-l-[3-(3-pyridm-3-ylisoxazol-5-yl)propyl]-l//-imidazo[4,5-c]qumo
amine as a white powder, mp 199.0-200.0 °C.
'H NMR (300 MHz, DMSO-rf tf ) 8 8.99 (d, J= 2.5 Hz, 1H), 8.66 (dd, J= 3.2, 1.7 Hz, 1H),
8.13 (dt, J= 8.2, 1.9 Hz, 1H), 7.83 (t, /= 8.0 Hz, 2H), 7.51 (t, J= 7.1 Hz, 1 H), 7.40 (m, 1
H), 7.29 (t, J= 7.0 Hz, 1 H), 6.44 (s, 1H), 5.45 (s, 2H), 4.80 (s, 2H), 4.68 (t, J= 7.9 Hz,
2H), 3.61 (q, 7= 7.0 Hz, 2H), 3.06 (t, J= 7.3 Hz, 2H), 2.47 (m, 2H), 1.23 (t, J= 7.0, 3H);
MS (APCI) m/z 429 (M + H) + ;
Anal, calcd for C 24 H24N 6 O 2 »0.4 H 2 0: C, 66.16; H, 5.74; N, 19.29. Found: C, 66.53; H,
5.70; N, 18.93.
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Example 7
2-(EthoxymethylH -[3-^
amine
Part A
Af-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of
Example 2, 2.61 g, 16.8 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-l-
pent-4-ynyl-l#-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6,
2.90 g, 839 mmol) and triethylamine (3.50 mL, 25.2 mmol) in dichloromethane at 6 °C.
The solution was heated at 50 °C under a nitrogen atmosphere for 4 hours. The solution
was diluted with dichloromethane, transferred to a separator/ funnel, washed with water
and brine, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was
triturated with hexanes and the solvent was decanted. The oil was triturated with diethyl
ether and a solid formed that was isolated by filtration to provide 4-chloro-2-
(ethoxymethyl)-l-[3-(3-phenylisox^ (1 .98 g).
The filtrate was purified by flash chromatography (silica gel, gradient elution from 7:3 to
1:1 hexanes/ethyl acetate) to provide an additional 0.24 g of product. The total amount of
4-chloro-2-(ethoxymethyl)-l -[3^
c]quinoline isolated was 2.22 g.
PartB
A mixture of 4-cWoro-2-(ethoxymethyl)-l-[3-(^
imidazo[4,5-c]quinoline (2.22 g, 4.97 mmol) in a solution of 7 M ammonia in methanol
(25 mL) was heated at 150 °C for 1 7 hours in a Parr pressure vessel. The volatiles were
removed under reduced pressure and the resulting solid was triturated with 1 M aqueous
sodium hydroxide and isolated by filtration. The crude product was purified by flash
chromatography (silica gel, gradient elution from 10% to 20% CMA in chloroform). The
appropriate fractions were combined and concentrated to yield a solid that was triturated
with hot diethyl ether and 9:1 dichloromethane/methanol (10 mL). The final material was
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dried at 80 °C under vacuum to yield 2-(ethoxymethyl)-l-[3-(3-phenybsoxazol-5-
yl)propyl]-l/f-inudazo[4,5-c]quinolin-4-amine (954 mg) as a white powder, mp 171.0-
172.0 °C.
! H NMR (300 MHz, DMSO-40 § 7.99 (d, J= 7.7 Hz, 1H), 7.83-7.85 (in, 2H), 7.62 (d, J=
5 7.4 Hz, 1H), 7.46-7.52 (m, 3H), 7.46 (t, J= 8.1 Hz, 1H), 7.21 (t, J= 7.0 Hz, 1H), 6.90 (s,
1H), 6.60 (s, 2H), 4.77 (s, 2H), 4.68 (t, 7= 7.8 Hz, 2H), 3.53 (q, /= 7.0 Hz, 2H), 3.09 (t, /
= 7.4 Hz, 2H), 2.30 (m, 2H), 1.12 (t, J= 7.0 Hz, 3H);
MS (APCI) m/z 428 (M + H) + ;
Anal, calcd for C25H25N5O2: C, 70.24; H, 5.89; N, 16.38. Found: C, 69.97; H, 6.02; N,
10 16.52.
Example 8
2-(Ethoxymemyl)-l-[3-(3-methylisoxazol-5-yl)propyl]-liy-imidazo[4,5-c]quinolin-4-
In the presence of triethylamine (5.2 mL, 10.7 mmol) in a solution of THF (50
mL), 4-cMoro-2-(emoxymethyl)-l-pent-4-ynyl-lif-inndazo[4,5-c]quinoline (prepared as
described in Part F of Example 6, 3.50 g, 10.7 mmol) was reacted with N-
20 hydroxyemanimidoyl chloride that was generated from acetaldehyde oxime (1 .90 g, 32. 1
mmol) and i^-chlorosuccinimide (4.30 g, 32.1 mmol) using the method described in Part B
of Example 5. The crude product was purified by flash chromatography (silica gel,
gradient elution with 4:1 to 2:3 hexanes/ethyl acetate). The appropriate fractions were
combined and concentrated to provide a sobd that was triturated with diethylether. The
25 solid was isolated by filtration and dried to yield 4-chloro-2-(ethoxymethyl)-l-[3-(3-
memylisoxazol-5-yl)propyl]-liy-imidazo[4,5-c]quinoline (1.87 g) as a white solid.
amine
NH 2
Part A
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PartB
4-Chloro-2-(ethoxymettiyl)- 1 -[3-(3-methylisoxazol-5-yl)propyl]4//^-imidazo[4,5-
c]quinoline (1 .87 g, 4.86 mmol) was treated with a solution of 7 M ammonia in methanol
(20 mL) according to the procedure described in Part C of Example 5. The crude product
was purified by flash chromatography (silica gel, gradient elution from 5% to 20% CMA
in chloroform). The appropriate fractions were combined and concentrated to yield a solid
that was triturated with 9:1 dichloromethane/methanol. The final material was dried under
vacuum to yield 2-(ethoxymethyl)4^3-(3-methyUso
c]quinolin-4-amine (1.29 mg) as a white powder, mp 163.0-164.0 °C.
*H NMR (300 MHz, DMSO-tf tf ) 8 7.95 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 7.6 Hz, 1H), 7.44
(t, J= 7.4 Hz, 1H), 7.22 (t, 7.5 Hz, 1H), 6.59 (s, 2H), 6.18 (s, 1H), 4.75 (s, 2H), 4.62 (t,
J- 7.7 Hz, 2H), 3.53 (q, /= 7.0 Hz, 2H), 2.96 (t, J= 7.4 Hz, 2H), 2.23 (m, 5H), 1.14 (t, J
= 7.0 Hz, 3H);
MS (APCI) m/z 366 (M 4- H) + ;
Anal, calcd for C20H23N5O2: C, 65.74; H, 6.34; N, 19.16. Found: C, 65.41; H, 6.41; N,
19.15.
Example 9 '
2-(Ethoxymethyl)-6,7-dimethyl-l-^
c]pyridin-4-amine
Part A
To dichloromethane (10 mL) at -78 °C was added dimethylsulfoxide (0.37 mL,
5.17 mmol) and oxalyl chloride (0.33 mL, 3.79 mmol). After several minutes, a solution
of 2-[8-(ethoxymethyl)-5 ,6-dimethyl-7i/-imidazo[4,5-c]tetraazolo[ 1 ,5-a]pyridin-7-
yl]ethanol (prepared as described in U.S. Patent No. 6,797,718, 1 .00 g, 3.44 mmol) in
dichloromethane (40 mL) was added dropwise followed by triethylamine (1.5 mL, 10.3
mmol). The mixture was allowed to warm to room temperature and more
dichloromethane (80 mL) was added. The solution was transferred to a separatory funnel
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and washed with saturated aqueous potassium carbonate, water, and brine. The aqueous
layers were combined and back-extracted with dichloromethane. The organic phases were
combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to
yield the product [8Kemoxymemyl)-5,6-dimethyl-7^-imidazo[4,5-c]tetraazolo[l,5-
a]pyridin-7-yl]acetaldehyde as a tan solid (0.86 g).
PartB
Diethyl l-diazo-2-oxopropylphosphonate (0.90 g, 3.6 mmol) was prepared by the
method of Bestmann, H. J. et al, Synlett, pp. 521-522 (1996) and added to a mixture of [8-
(emoxymemyl)-5,6-dimemyl-7/f-imidazo[4,5-e]tetraazolo[l,5-a]pyridin-7-
yfjacetaldehyde (0.86 g, 3.0 mmol) and potassium carbonate (0.82 g, 6.0 mmol) in
methanol (1 0 mL) at room temperature. After 2.5 hours, the reaction was filtered and the
filter cake was rinsed with a mixture of dichloromethane and methanol. The filtrate was
diluted with dichloromethane and washed with water (2 x) and brine (2 x). The aqueous
phases were combined and back-extracted with dichloromethane. The organic portions
were combined, dried over magnesium sulfate, filtered, and concentrated. The yellow
solid was triturated with diethyl ether and dried under vacuum to provide the slight impure
product 8-(emoxymethyl)-5,6-dime%l-7-prop-2-ynyl-7/y-imidazo[4,5-c]tetraazolo[l,5-
ajpyridine (0.442 g) that was used without further purification.
PartC
In the presence of triemylamine (0.50 mL, 3.4 mmol), 8-(ethoxymethyl)-5,6-
dimemyl-7-prop-2-ynyl-7iy-imidazo[4,5-c]tetraazolo[l,5-a]pyridine (0.442 g, 1.55 mmol)
was reacted with ^-hydroxypyridine-3-carboximidoyl chloride generated from 3-
pyridinecarboxyaldehyde oxime (prepared as described in Part A of Example 5, 0.38 g,
3.1 1 mmol) and W-cMorosuccinimide (0.42 g, 3.1 1 mmol) in THF (5 mL) using the
method described in Part B of Example 5. After purification by flash chromatography
(silica gel, elution with 95:5 dichloromethane/methanol) and trituration in diethyl ether,
the product 8<emoxymemyl)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-7F-
imidazo[4,5-c]tetraazolo[l,5-a]pyridine was obtained (0.171 g) as a white powder.
PartD
A mixture of 8-(ethoxyme%l)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-
yl)memyl]-7//-imidazo[4,5-c]tetraazolo[l,5-fl]pyridine (0.1712 g, 0.423 mmol) and
triphenylphosphine (0.120 g, 0.466 mmol) in toluene (2 mL) was heated at reflux for five
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days. The solvent was removed and the resulting brown solvent was dissolved in 1 M
hydrogen chloride in methanol (5 mL). The solution was heated at reflux for four hours
and then concentrated to an oil. The oil was dissolved in hot water. A precipitate formed
and was isolated by filtration. The filtrate was washed five times with dichloromethane
5 and then adjusted to pH 14 with 50% (w/w) aqueous sodium hydroxide, resulting in a
brown precipitate. The mixture was extracted with several portions of dichloromethane
that were combined, washed with water and brine, dried over magnesium sulfate, filtered,
and concentrated. The resulting white solid was triturated with diethyl ether and dried to
yield 2-(ethoxymethyl)-6,7-dimethyl- 1 -[(3-pyridin-3-ylisoxazol-5-yl)methyl]- IH-
10 imidazo[4,5-c]pyridin-4-amine as a white powder, mp 189.0-191 .0 °C.
*H NMR (300 MHz, DMSO-rf*) 5 9.04 (d, J= 1.5 Hz, 1H), 8.66 (dd, J= 3.2, 1.6 Hz, 1H),
8.23 (dt, J= 8.0, 1.8 Hz, 1H), 7.48-7.52 (m, 1H), 6.92 (s, 1H), 5.91 (s, 2H), 5.86 (s, 2H),
4.74 (s, 2H), 3.45 (q, 7= 7.0 Hz, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 0.97 (t, J= 7.0 Hz, 3H);
MS (APCI) m/z 379 (M + H) + ;
15 Anal, calcd for C20H22N6O2: C, 63.48; H, 5.86; N, 22.21. Found: C, 63.20; H, 6.03; N,
21.94.
Example 10
2~Ethoxymetliyl-l -[2-^
20 c]quinolin-4-amine
Part A
1,2-Diaminoethane (7.55 mL, 113 mmol) was added to a 0 °C solution of 2,4-
dichloro-3-nitroquinoline (28.9 g, 119 mmol) and triethylamine (24.9 mL, 179 mmol) in
25 dichloromethane (600 mL). The solution was allowed to warm slowly to room
temperature and stir for 20 hours. The solvent was removed under reduced pressure and
5% aqueous Na2C03 (300 mL) was added. The resulting slurry was stirred vigorously at 0
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°C for four hours. A yellow solid was isolated by vacuum filtration and dried under
vacuum. The solid was purified by suction filter chromatography (silica gel, gradient
elution from 98:2 to 93:7 dichloromethane/methanol) to provide the product iV-(2-chloro-
3-nitroquinolin-4-yl)ethane-l,2-diamine (16.0 g) that contained a small amount of an
5 impurity.
PartB
Triethylamine (3.12 mL, 22.4 mmol) was added to a slurry of N-(2-chloro-3-
nitroquinolin-4-yl)ethane-l,2-diamine (3.00 g, 1 1.2 mmol) in dichloromethane (80 mL).
A solution of di-ter/-butyl carbonate (2.95 g, 13.5 mmol) in dichloromethane (20 mL) was
10 added over 5 minutes to the slurry. The solution was stirred at room temperature for three
hours and then was partitioned between dichloromethane and saturated aqueous sodium
bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers
were combined and washed with brine, dried over magnesium sulfate, filtered, and
concentrated to an orange solid. The crude product was purified by flash chromatography
15 (silica gel, 3:1 hexanes/ethyl acetate as the eluent) to afford fert-butyl 2-[(2-chloro-3-
nitroquinolin-4-yl)amino]ethylcarbamate (3.70 g) as a bright yellow solid.
PartC
A solution of Na 2 S 2 0 4 (10.3 g, 50.4 mmol) in water (40 mL) was added to a
solution of tert-butyl 2-[(2-cMoro-3-nitroquinohn-4-yl)amino]ethylcarbamate (3.70 g, 10.1
20 mmol). A white solid precipitated immediately and after 30 min the precipitate was
removed by filtration. The filtrate was concentrated under reduced pressure, was diluted
with saturated aqueous sodium bicarbonate, and was extracted with dichloromethane three
times. The combined organic layers were washed with brine, dried over magnesium
sulfate, filtered, and concentrated to a pale yellow oil. Purification by flash
25 chromatography (silica gel, gradient elution with 2: 1 to 1 : 1 hexanes/ethyl acetate) afforded
tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (2.14 g) as a colorless
oil.
PartD
A solution of ethoxyacetyl chloride (857 mg, 6.99 mmol) in acetonitrile (5 mL)
30 was added to solution of /ert-butyl 2-[(3-amino-2-chloroquinolin-4-
yl)amino]ethylcarbamate (2.14 g, 6.35 mmol) in acetonitrile (20 mL). After five minutes,
the solution was cooled in an ice bath and a white precipitate began to form. After one
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hour, the precipitate was isolated by filtration and dried under vacuum to afford the
hydrochloride salt of tert-butyl 2-( {2-chloro-3-[(ethoxyacetyl)amino]quinolin-4-
yl}amino)ethylcarbamate (2.50 g).
PartE
5 To a solution of the hydrochloride salt of tert-butyl 2-({2-chloro-3-
[(ethoxyacetyl)amino]quinolin-4-yl}amino)ethylcarbamate (2.50 g, 5.44 mmol) in 9:1
ethanol/water (50 mL) was added a solution of potassium carbonate (1.12 g, 8.16 mmol) in
water (5 mL). The solution was heated to 50 °C for five hours. The solution was
concentrated under reduced pressure and the residue was partitioned between saturated
10 aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with
two additional portions of dichloromethane. The combined organic layers were washed
with brine, dried over magnesium sulfate, filtered, and concentrated to a pale yellow solid
that was purified by flash chromatography (silica gel, gradient elution from 1:1 to 4:1
ethyl acetate/hexane) to afford the tert-butyl 2-(4-chloro-2-ethoxymethyl-li/-imidazo[4,5-
15 c]quinolin-l-yl]ethylcarbamate as a white solid (1 .55 g).
PartF
A solution of tert-butyl 2-(4>cMoro-2-ethoxymethyl-liy-imidazo[4,5-c]quinolin-l-
yl]ethylcarbamate (1.55 g, 3.83 mmol) in a solution of 4 M hydrogen chloride in dioxane
(15 mL) was stirred at room temperature for two hours. An aqueous solution of 2 M
20 sodium hydroxide was added to adjust the reaction to pH 13. The solution was extracted
with several portions of dichloromethane. The combined organic layers were washed with
brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was
purified by flash chromatography (silica gel, gradient elution from 97:3 to 97:5
dichloromethane/methanol) to afford 2-(4-chloro-2-ethoxymethyl-l//-imidazo[4,5-
25 c]quinolin-l-yl)ethylamine (760 mg) as a white solid.
PartG
A mixture of 2-(4-chloro-2-ethoxymethyl-l^-imidazo[4,5-c]quinolin-l-
yl)ethylamine (760 mg, 2.49 mmol) and magnesium sulfate in 9:1
dichloromethane/acetone was stirred at room temperature for four hours. The mixture was
30 filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane
(20 mL) and added to JV-hydroxyethanimidoyl chloride (3.11 mmol). The 7V-
hydroxyethanimidoyl chloride was prepared as follows: to a 0 °C solution of acetaldehyde
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oxime (184 mg, 3.1 1 mmol) in DMF (10 mL) was added A^chlorosuccinimide (415 mg,
3.1 1 mmol) over a period of five minutes. After 1 5 minutes, the solution was warmed to
50 °C for one hour. The solution was partitioned between water and ethyl acetate. The
aqueous layer was extracted with two additional portions of ethyl acetate. The combined
5 organic layers were washed with water and brine, dried over magnesium sulfate, filtered,
and concentrated to provide N-hydroxyethanimidoyl chloride as a pale yellow oil. The
dichloromethane solution from above was cooled in an ice bath and triethyamine (0.52
mL, 3.73 mmol) was added, resulting in the formation of a white precipitate. The mixture
was allowed to warm slowly to room temperature and stir overnight. The solution was
1 0 washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium
sulfate, filtered, and concentrated. The crude product was purified by flash
chromatography (silica gel, gradient elution from 98:2 to 96:4 dichloromethane/methanol)
to yield 4-cMoro-2-ethoxymethyl-l-[2^
li/-imidazo[4,5-c]quinoline (680 mg) as a white solid.
15 PartH
A slurry of 4-chloro-2-ethoxymethyl-l-[2-(3,5,5-^
yl)ethyl]-l/f-imidazo[4,5-c]quinoline (670 mg, 1.67 mmol) in a solution of 7 M ammonia
in methanol (20 mL) was sealed in a pressure vessel and heated to 150 °C. After 15 hours,
the volatiles were removed under reduced pressure and the residue was partitioned
20 between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer
was extracted with two additional portions of dichloromethane. The combined organic
layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated.
The crude product was purified by flash chromatography (silica gel, gradient elution from
97:3 to 95:5 dichloromethane/methanol) to afford 2-ethoxymethyl-l-[2-(3,5,5-trimethyl-
25 l,2,4-oxadiazol-4(5i^-yl)ethyl]-^ (350 mg) as a white
solid that was recrystallized from acetonitrile to give white needles, mp 204-205 °C.
*H NMR (300 MHz, CDC1 3 ) 6 7.96 (dd, /== 8.2, 1 .0 Hz, 1H), 7.86 (dd, J= 8.4, 1 .0 Hz,
1H), 7.57 (ddd, J= 8.4, 7.1, 1.3 Hz, 1H), 7.35 (ddd, /= 8.3, 7.1, 1.3 Hz, 1H), 5.46 (br s,
2H), 4.83 (s, 2H), 4.80 (t, J= 6.9 Hz, 2H), 3.66-3.57 (m, 4H), 1.85 (s, 3H), 1.39 (s, 6H),
30 1.25(t,J=7.0Hz,3H);
MS (APCI) m/z 383 (M + H*);
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Anal, calcd for C20H26N6O2: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.83; H, 7.20; N,
22.13.
Example 1 1
5 1 - { [3-(4-Fluorophenyl)isoxazol-5-yl]methyl} - 1 #-imidazo[4,5 -c] [ 1 ,5]naphthyridin-4-
amine
F
Part A
Propargylamine (54 mL, 0.98 mol) was added over a period of one hour to a
10 suspension of 4-chloro-3-nitro[l,5]naphthyridine (186.4 g, 0.889 mol) and triethylamine
(186 mL, 1 .33 mol) in THF (1 L) while maintaining the reaction temperature at 25 °C.
The reactioh was stirred for 45 minutes, and then deionized water (21 mL per gram of
expected product) was added. The resulting suspension was stirred for about one hour and
filtered to isolate a solid. The solid was washed with water until the filtrate was pH
1 5 neutral and then dried under vacuum at 65 °C to provide 1 8 1 .2 g of 3-nitro-7V»prop-2-
ynyl[l,5]naphthyridin-4-amine as a brown solid.
PartB
Aqueous sodium hydroxide (70 mL of 50% w/w) was added to a solution of 4-
fluorobenzaldehyde (140.5 g, 1.132 mol) and hydroxylamine hydrochloride (86.5 g, 1.25
20 mol) in ethanol (1 L) and water (2 L), and the reaction was stirred at room temperature for
one hour and then adjusted to pH 14 with the addition of 50% w/w aqueous sodium
hydroxide. The mixture was extracted with several portions of dichloromethane and then
several portions of chloroform. The combined extracts were concentrated under reduced
pressure approximately one liter, filtered through a layer of CELITE filter agent and
25 sodium sulfate, and concentrated again under reduced pressure to yield 127 g of 4-
fluorobenzaldehyde oxime as a white solid.
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PartC
N-Chlorosuccinimide (85.5 g, 438 mmol) was added to a solution of 4-
fluorobenzaldehyde oxime (61.0 g, 438 mmol) in DMF (100 mL) at room temperature; an
exotherm occurred. After the addition, the solution was heated at 40 °C for 30 minutes
under nitrogen. The solution was poured onto ice and extracted with chloroform. The
combined extracts were washed with brine, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure, and further dried under high vacuum for 16 hours to
provide 52.23 g of 4-fluoro-JV-hydroxybenzenecarboximidoyl chloride as an amber oil.
PartD
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride
(7.6 g, 44 mmol) was added to a heated solution (40 °C) of 3-nitro~JV-prop-2-
ynyl[l,5]naphthyridin-4-amine (5.0 g, 22 mmol) and anhydrous triethylamine (6.7 mL, 48
mmol) in anhydrous dichloromethane (150 mL). The reaction was heated at 40 °C for 1.7
hours and then concentrated under reduced pressure. The residue was triturated with
water; the resulting solid was isolated by filtration, washed sequentially with toluene and a
small amount of diethyl ether, and then dissolved in dichloromethane. The solution was
concentrated under reduced pressure and dried under high vacuum to provide 6.00 g ofN-
{[3-(4-fluorophenyl)isoxazol-5-yl]m^ as a
brownish-yellow solid.
PartE
A Parr vessel was charged with 5% platinum on carbon (0.12 g), purged with
nitrogen, and then charged sequentially with toluene (2 mL), 7V-{[3-(4-
fluorophenyl)isoxazol-5-yl]methy^ (6.00 g, 16.4
mmol), toluene (73 mL), and isopropanol (5 mL). The vessel was purged with hydrogen
three times and then placed under hydrogen pressure (50 psi, 3.4 x 10 5 Pa) for 16 hours.
An analysis by high-performance liquid chromatography (HPLC) indicated the presence
of starting material. The catalyst was removed by filtration and washed with hot
dichloromethane and methanol. The filtrate was concentrated under reduced pressure, and
the residue was dissolved in hot methanol (100 mL) and added to a Parr vessel. Catalytic
5% platinum on carbon (0.12 g) was added, and the reaction was placed under hydrogen
pressure (50 psi, 3.4 x 10 5 Pa) for four hours. The catalyst was removed by filtration, and
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the filtrate was concentrated under reduced pressure to provide N*-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl} [ 1 ,5]naphthyridine-3,4-diamine.
PartF
Triethyl orthoformate (4.1 mL, 25 mmol) was added to a solution of the material
5 from Part E and pyridine hydrochloride (0.04 g, 0.3 mmol) in toluene (1 L), and the
reaction was heated at 1 10 °C in a nitrogen atmosphere for 1.5 hours. A Dean-Stark trap
was used to collect the volatiles. The reaction mixture was then concentrated under
reduced pressure, and the residue was partitioned between dichloromethane and 1 N
aqueous sodium hydroxide. The aqueous fraction was extracted several times with
10 dichloromethane, and the combined organic fractions were washed with water and brine,
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The
resulting solid was triturated with a mixture of diethyl ether and hexane, isolated by
filtration, and dried under vacuum to provide 2.76 g of l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-l^-imidazo[4,5-c][l,5]naphthyridine as a green powder.
15 PartG
3-Chloroperoxybenzoic acid (mCPBA) (2.4 g of 75% pure material) was added to
a suspension of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l J H r -imidazo[4,5-
c][l,5]naphthyridine (2.76 g, 7.99 mmol) in dichloromethane (100 mL). The reaction was
stirred at room temperature for 30 minutes; an analysis by TLC then indicated the
20 presence of starting material. Additional mCPB A (0.065 g of 75%) was added, and the
reaction was stirred for another 30 minutes and found to be complete by TLC analysis.
Concentrated ammonium hydroxide (50 mL) and /?-toluenesulfonyl chloride (1.68 g, 8.79
mmol) were sequentially added. The mixture was stirred for 30 minutes. The volatiles
were removed under reduced pressure, and 1 N aqueous sodium hydroxide and water were
25 added to the resulting mixture, which was filtered to isolate a solid. The solid was washed
with diethyl ether. Additional solid precipitated from the aqueous filtrate, and was
isolated by filtration and combined with the first solid to provide 2.48 g of l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl} -5-oxido- 1/f-imidazo [4,5-c] [ 1 ,5]naphthyridine, which
was dissolved in a mixture of methanol (80 mL) and dichloromethane (80 mL). The
30 resulting mixture was heated to 50 °C, and concentrated ammonium hydroxide (20 mL)
and benzenesulfonyl chloride (1.2 mL, 7.6 mmol) were added. The reaction was heated
under a nitrogen atmosphere for one hour, and additional benzenesulfonyl chloride (0.5
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mL) was added. The solvents were removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluting with 2% to 10% CMA in
chloroform) followed by recrystallization from acetonitrile to provide 0.612 g of l-{[3-(4-
fluorophenyl)isoxazol-5-yl]memyl}-l^M
white solid, mp 265.0 -266.0 °C.
MS (ESI) m/z 361 (M + H)+;
Anal, calcd for C19H13FN6O: C, 63.33; H, 3.64; N, 23.32. Found: C, 63.20; H, 3.68; N,
23.43.
Example 12
2-(Emoxymethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-yl]me%l}-l/^imidazo[4,5-
c] [1 ,5]naphthyridin-4-amine
NH,
F
Part A
Under a nitrogen atmosphere, 4-fluoro-A^hydroxybenzenecarboximidoyl chloride
(44.6 g, 257 mmol) was added to a mixture of 3-nitro-AT-prop-2-ynyl[l,5]naphmyridin-4-
amine (29.34 g, 129 mmol) and anhydrous triethylamine (39.5 mL, 283 mmol) in
anhydrous dichloromethane (1 L). The reaction was stirred at 40 °C for 18 hours and then
concentrated under reduced pressure. The residue was triturated with water; the resulting
solid was isolated by filtration, washed sequentially with isopropanol and a small amount
of diethyl ether, and then dried under vacuum to provide 15.02 g of i\T-{[3-(4-
fluorophenyl)isoxazol-5-yl]memyl}-3-mfro[l,5]naphthyridin-4-aniine as a brownish-green
solid.
PartB
A solution ofN-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-
nitro[l,5]naphthyridin-4-amine (15.02 g, 41.1 1 mmol) in hot methanol (4 L) was filtered
to remove a solid and then added to a Parr vessel charged with 5% platinum on carbon
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(1 .5 g) that had been purged with nitrogen and wet with methanol (50 mL). The vessel
was purged with hydrogen three times and then placed under hydrogen pressure (25 psi,
1 .7 x 10 5 Pa) for 12 hours. The catalyst was removed by filtration and washed with a
mixture of dichloromethane and methanol, and the filtrate was concentrated under reduced
5 pressure to provide 8.3 g of ^-{[S-^-fluorophenytyisoxazol-S-
yl]methyl}[l,5]naphthyridine-3,4-diamine containing an impurity.
PartC
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.6 g, 13 mmol) was added
over a period of ten minutes to a cooled (6 °C) solution of N*-{[3-(4-
1 0 fluorophenyl)isoxazol-5-yl]methyl} [ 1 ,5]naphthyridine-3,4-diamine (4. 1 g, 1 2 mmol) and
anhydrous triethylamine (2.6 mL, 18 mmol) in anhydrous dichloromethane (150 mL).
After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence
of starting material, and additional ethoxyacetyl chloride (1.1 g) was added. The reaction
was stirred for an additional 30 minutes and then was diluted with dichloromethane and
15 washed with saturated aqueous potassium carbonate. The aqueous layer was separated
and extracted with dichloromethane, and the combined organic fractions were washed
with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced
pressure to afford 2-ethoxy-i\T-[4-({[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}amino)[l,5]naphthyridin-3-yl]acetoiide as a black oil.
20 PartD
A solution of the material from Part C and pyridine hydrochloride (0.028 g, 0.24
mmol) in toluene (100 mL) was heated at 1 10 °C under a nitrogen atmosphere for 22.5
hours. The volatiles were removed under reduced pressure, and the residue was dissolved
in dichloromethane. The solution was washed sequentially with saturated aqueous
25 potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluting with ethyl acetate) and then triturated with a mixture
of diethyl ether and hexane and isolated by filtration to provide 1 .74 g of 2-
(ethoxymethyl)-l-{[3-(4-fluoroph
30 c] [ 1 ,5]naphthyridine.
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PartE
mCPBA (1 .7 g of 75% pure material) was added to a solution of 2-(ethoxymethyl)- .
1- {[3-(4-fluorophenyl)isoxazol-5-yl]methyl} -l#-imidazo[4,5-c][l ,5]naphthyridine (1 .74
g, 4.31 mmol) in dichloromethane (50 mL). The reaction was stirred at room temperature
for 30 minutes; an analysis by TLC then indicated the presence of starting material.
Additional mCPBA (0.25 g of 75%) was added, and the reaction was stirred for another 30
minutes and found to be complete. The solvent was removed under reduced pressure, and
the residue was triturated with diethyl ether and isolated by filtration to provide 1.64 g of
2- (ethoxymethyl> 1 - {[3-(4-fluorophenyl)isoxazol-5-yl]methyl} -5-oxido- l#-imidazo[4,5-
c][l,5]naphthyridine as a pale yellow solid.
PartF
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl} -5-oxido- l#-imidazo[4,5-c] [ 1 ,5]naphthyridine ( 1 .64 g,
3.90 mmol) in anhydrous dichloromethane (50 mL) was cooled to 6 °C, and a solution of
trichloroacetyl isocyanate (0.51 mL, 4.29 mmol) in dichloromethane (5 mL) was added
dropwise. The solution was stirred for 30 minutes, and then the solvent was removed
under reduced pressure. The residue was treated with sodium methoxide in methanol (10
mL of a 25% w/w solution) and methanol (40 mL). The resulting mixture was stirred for
1 8 hours at room temperature. A precipitate was present and was isolated by filtration,
washed with methanol and diethyl ether, and dried under high vacuum at 80 °C for 18
hours to provide 0.999 g of 2-(ethoxymethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-l//-imidazo[4,5-c][l,5]naphthyridin-4-amine as a white solid, mp 190.0 -
191.0 °C.
MS (ESI) m/z 419 (M + H)+;
Anal, calcd for C 2 2Hi9FN 6 O2-0.3H2O: C, 62.35; H, 4.66; N, 19.83. Found: C, 62.05; H,
4.28; N, 19.71.
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Example 13
l-{[3-(4-Fluorophenyl)isoxazol-5-yl]^^
c] [ 1 ,5]naphthyridin-4-amine
F
5 Part A
Triethyl orthoacetate (2.8 mL, 15.2 mmol) was added to a solution of A^-{[3»(4-
fluorophenyl)isoxazol-5-yl]methyl}[l,5]naphthyridine-3,4-diamine (prepared in Part B of
Example 12, 3.4 g, 10.1 mmol) and pyridine hydrochloride (0.023 g, 0.20 mmol) in
toluene (100 mL), and the reaction was heated at 1 10 °C under a nitrogen atmosphere for
10 15.5 hours. The reaction mixture was then concentrated under reduced pressure, and the
residue was dissolved in dichloromethane. The work-up and purification procedures
described in Part D of Example 12 were followed with the modification that the silica
column was eluted with 5% methanol in ethyl acetate. l-{[3-(4-Fluorophenyl)isoxazol-5-
yl]methyl}-2-methyl-li/-imidazo[4,5-c][l 5 5]naphthyridine (1.15 g) was obtained as a light
15 gray solid.
PartB
The method described in Part E of Example 12 was used to treat l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl} -2-methyl-l#-imidazo[4,5-c] [ 1 ,5]naphthyridine (1.15
g, 3.20 mmol) with mCPBA (0.94 g of 75% pure material followed by 0.25 g) to provide
20 l-{[3K4-fluorophenyl)isoxazol-5-yl]^
c][l,5]naphthyridine as a dark yellow solid.
PartC
The method described in Part F of Example 12 was followed using the material
from Part B as the starting material with the modification that the reaction with sodium
25 methoxide was stirred for 20 hours and found to be incomplete as evidenced by HPLC
analysis. Additional sodium methoxide (15 mL of a 25% w/w solution in methanol) was
added, and the reaction was stirred for an additional 16 hours. After the solid product was
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filtered and washed, it was recrystallized from acetonitrile and dried under high vacuum at
80 °C to provide 0.253 g of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-l//-
imidazo[4,5-c][l,5]naphthyridin-4-amine as a white solid, mp 239.0 - 240.0 °C.
MS (ESI) m/z 375 (M + H)+;
Anal, calcd for C 2 oHi 5 FN 6 0: C, 64.17; H, 4.04; N, 22.45. Found: C, 64.01; H, 3.95; N,
22.50.
Example 14
l-{[3-(4-Fluorophenyl)isoxazol-5-yl]me%l}-2-propyl-l/^imidazo[4,5-
c][l ,5]naphthyridin-4-amine
F
Part A
The methods described in Part A of Example 13 were used to treat iV 4 -{[3-(4-
fluorophenyl)isoxazoI"5-yl]methyl}[l,5]naphthyridine-3,4-diamine (2.6 g, 7.8 mmol) with
trimethyl orthobutyrate (1.9 mL, 12 mmol) in the presence of pyrdine hydrochloride
(0.018 g, 0.16 mmol) and isolated and purify the final product with the modification that
the silica column was eluting with 60-90% ethyl acetate in dichloromethane. 1 - {[3-(4-
Fluorophenyl)isoxazol-5^^
g) was obtained as a white solid.
PartB
The method described in Part E of Example 12 was used to treat l-{[3-(4-
fluorophenyl)isoxazol-5-yl]m^^
g, 2.79 mmol) with mCPBA (1.1 g of 75% pure material followed by 0.35 g) with the
modification that the trituration of the crude product was carried out with diethyl ether. 1-
{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}"5-oxido-2-propyl-lH-imidazo[4,5-
c][l,5]naphthyridine was obtained as a white solid.
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PartC
The method described in Part F of Example 12 was followed using the material
from Part B as the starting material with the modification that 40 mL of 25% w/w sodium
methoxide in methanol were used in the second step with no additional methanol; the
reaction was complete in 2.7 hours. After the solid product was filtered and washed, it
was recrystallized from toluene and dried to provide 0.439 g of l-{[3-(4-
fluorophenyl)isoxazol-5-yl]me%l^
amine as a white solid, mp 238.0 - 239.0 °C.
MS (ESI) m/z 403 (M + H)+;
Anal, calcd for C22H 19 FN 6 0: C, 65.66; H, 4.76; N, 20.88. Found: C, 65.82; H, 4.74; N,
20.79.
Example 15
(4-Ammo-l- {[3-(4-fluorophenyl^^
c] [ 1 ,5]naphthyridin-2-yl)methanol
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl>l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}-l^-imidazo[4,5-c][l ,5]naphthyridin-4-amine (0.40 g,
0.96 mmol) in dichloromethane (25 mL) was cooled on an ice bath, and boron tribromide
(2.4 mL of a 1 M solution in dichloromethane) was added. The reaction was stiired for 17
hours, and an analysis by HPLC indicated the presence of starting material. Additional
boron tribromide (1 mL) was added after 17 hours and then again after 32 hours of
reaction time. After 32 hours of reaction time, methanol was added, and the solvents were
removed under reduced pressure. The residue was triturated with water, isolated by
filtration, washed with diethyl ether, recrystallized from methanol, and dried under high
vacuum at 100 °C to provide 0.14 g of (4-amino-l-{[3-(4-fluorophenyl)isoxazol-5-
NH.
F
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yl]methyl}-l#-imidazo[4,5-c][l,5]m as a white solid, mp 247.0
- 248.0 °C.
MS (ESI) m/z 391 (M + H)+;
Anal, calcd for C2oH I5 FN 6 02: C, 61.54; H, 3.87; N, 21.53. Found: C, 61.26; H, 3.90; N,
21.60.
Example 16
2-(Ethoxymethyl)-l-[2-(3^
imidazo[4,5-c]quinolin-4-amine
Part A
A mixture of 2-(4-chloro-2-ethoxymethyl-l//-imidazo[4,5-c]quinolin-l-
yl)ethylamine (1.00 g, 3.28 mmol), cyclopentanone (0.32 mL, 3.6 mmol), and magnesium
sulfate in dichloromethane was stirred at room temperature overnight. The mixture was
filtered and the filtrate was concentrated under reduced pressure. The residue was
dissolved in dichloromethane (20 mL) along with N-hydroxyethanimidoyl chloride, which
was prepared from acetaldehyde oxime (242 mg, 4.10 mmol) and JV-chlorosuccinimide
(537 mg, 4.10 mmol) according to the method described in Part G of Example 10. The
resulting solution was cooled in an ice bath and triethylamine (0.69 mL, 4.9 mmol) was
added. The mixture was allowed to warm slowly to room temperature and stirred
overnight. The work-up and purification procedures described in Part G of Example 10
were followed to provide 770 mg of 4-chloro-2-(ethoxymethyl)-l-[2-(3-methyl-l-oxa-2,4-
diazaspiro[4.4]non-2-en-4-yl)ethyl]-l/f-imidazo[4,5-c]quinoline as a clear, colorless oil-
Part B
The methods described in Part H of Example 10 were used to treat 4-chloro-2-
(ethoxymethyl)- 1 -[2-(3-methyl- 1 -oxa-2,4-diazaspko[4.4]non-2-en-4-yl) ethyl]-l#-
imidazo[4,5-c]quinoline (770 mg, 1.80 mmol) with a solution of 7 M ammonia in
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methanol (20 mL) and isolate and purify the final product to provide 700 mg of 2-
(ethoxyme%l)-H2-(3-methyM
imidazo[4,5-c]quholin-4-amine as white needles, mp 21 1-213 °C.
MS (APCT) rn/z 409 (M + H 4 );
Anal, calcd for C 2 2H28N 6 0 2 : C, 64.69; H, 6.91- N, 20.57. Found: C, 64.47; H, 7.08; N,
20.83.
Example 17
l-{[3K 4 -Fluorophenyl)isoxazol-^
c] [ 1 ,5]naphthyridin-4-amine
F
1 - {[3^4-Fluorophenyl)isoxazol-5^
4-amine (Example 11, 0.300 g, 0.833 mmol) was combined with platinum (IV) oxide
(0.03 g) and trifluoroacetic acid (5 mL), and the mixture was placed under hydrogen
pressure (45 psi, 3.1 x 10 5 Pa) for 24 hours. An analysis by liquid chromatography/mass
spectrometry indicated the presence of starting material. The catalyst was removed by
filtration, and the trifluoroacetic acid was removed under reduced pressure. The residue
was combined with trifluoroacetic acid (5 mL) and platinum (IV) oxide (0.10 g), and the
reaction was again placed under hydrogen pressure (45 psi, 3.1 x 10 5 Pa) for 24 hours.
The catalyst was removed by filtration, and the trifluoroacetic acid was removed under
reduced pressure. The resulting oil was dissolved in 6 N hydrogen chloride in ethanol and
stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue
was dissolved in water. The solution was adjusted to pH 14 with the addition of a few
drops of 50% w/w sodium hydroxide, and the resulting mixture was stirred for 30 minutes.
A precipitate was present and was isolated by filtration, purified by column
chromatography on silica gel (5% to 10% CMA in chloroform), triturated with diethyl
ether, filtered, and dried to provide 0.0382 g of l-{[3-(4-fluorophenyl)isoxazol-5-
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yl]me%l}-6,7,8,9-tetrahydro-l^-imidazo[4 5 5-c][l,5]naphthyridin-4-amine as a white
powder, mp 227.0 - 228.0 °C.
MS (ESI) m/z 365 (M + H)+;
Anal, calcd for CgHnFNgO: C, 62.63; H, 4.70; N, 23.06. Found: C, 62.38; H, 4.62; N,
23.38.
Example 18
l-{[3-(4-Fluorophenyl)isoxazol-5-yl]me%^
amine
NH,
Part A
Under a nitrogen atmosphere, a solution of 2,4-dichloro-5,6-dimethyl-3-
nitropyridine (137.9 g, 0.624 mol) in anhydrous DMF (1.4 L) was cooled to 0 °C, and
anhydrous triethylamine (109 mL, 0.780 mol) was added. Propargyl amine hydrochloride
(4.72 g, 51.6 mmol) and propargyl amine (38.4 g, 0.697 mol) were sequentially added
dropwise, and the reaction was allowed to warm to room temperature and then heated at
40 °C for 22 hours. The volatiles were removed under reduced pressure, and water (1 .5 L)
and solid sodium carbonate (75 g) were added to the resulting oil. The mixture was then
extracted with dichloromethane, and the combined extracts were washed sequentially with
water and brine, dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography on silica gel (eluting
sequentially with 60:40 dichloromethane/hexane and dichloromethane) to provide 51.54 g
of 2-cWoro-5,6-dimethyl-3-nitro-^-prop-2-ynylpyridin-4-amine as a brown solid.
PartB
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride
(52.0 g, 225 mmol), prepared as described in Parts A through C of Example 1 1, was added
to a solution of 2-chloro-5,6-dimemyl-3-nitro-^-prop-2-ynylpyrioUn-4-aniine (26.92 g,
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1123 mmol) in anhydrous dichloromethane (1 L) at room temperature. Triethylamine (25
g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40 °C
under nitrogen for 16 hours, diluted with dichloromethane, washed sequentially with
aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and
5 concentrated under reduced pressure to a suspension. The suspension was filtered to
isolate a yellow solid, which was washed with diethyl ether and dried under vacuum to
provide 32.45 g of 2-cltforo-^{[3<4-fluorophen
nitropyridin-4-amine.
PartC
1 0 Under a nitrogen atmosphere, 2-chloro-N- {[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine (25.00 g, 66.35 mmol), toluene (250 mL),
triethylamine (11.1 mL, 79.6 mmol), and ^-bis(4-methoxybenzyl)amine (18.8 g, 73.0
mmol) were combined and heated at reflux for three days. The volatiles were removed
under reduced pressure, and the residue was partitioned between ethyl acetate and
15 saturated aqueous potassium carbonate. The ethyl acetate layer was separated and
concentrated under reduced pressure. The residue was dissolved in dichloromethane, and
the resulting solution was washed sequentially with water and brine. The combined
aqueous fractions were extracted with ethyl acetate. The combined organic fractions were
dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude
20 solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to
provide 37.29 g of A^-{[3-(4-fluorophenyl)isoxazol-5-yl]me%l}-7V 2 ^V 2 -bis(4-
methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-diamine as an orange solid.
PartD
Under a nitrogen atmosphere, toluene (2 L) was added to a Parr vessel containing
25 5% platinum on carbon (3.6 g). TV 4 - {[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-Ar 2 ,iV 2 -
bis(4-methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-dianiine (36.85 g, 61.66 mmol)
was added followed by ethanol (300 mL). The vessel was sealed, purged with hydrogen,
and placed under hydrogen pressure (30 psi, 2.1 x 10 5 Pa) for 18 hours at room
temperature. The catalyst was removed by filtration, and the filtrate was concentrated
30 under reduced pressure to provide 39.25 g of TV 4 - {[3-(4-fluorophenyl)isoxazol-5-
yl]me%l}-A^ 2 ^ 2 -bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3 as a yellow
oil.
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PartE
N*- {[3-(4-Fluorophenyl)isoxazol-5-yl]methyl} -N 2 ,A^-bis(4-methoxybenzyl)-5,6-
dimethylpyridine-2,3,44riamine (6.00 g, 10.6 mmol), triethyl orthofonnate (2.6 mL, 16
mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined at
5 heated at reflux for 24 hours. An analysis by HPLC indicated the reaction was
incomplete. Therefore, pyridine hydrochloride (0.25 g) was added, and the reaction vessel
was fitted with a Dean-Stark trap. The reaction was heated at reflux for an additional 1.8
days, and additional triethyl orthofonnate (1 mL) was added and heating was resumed.
After the reaction was heated for a total of three days, it was allowed to cool to room
1 0 temperature, and concentrated under reduced pressure. The residue was dissolved in
dichloromethane, and the resulting solution was washed sequentially with aqueous
potassium carbonate, water, and brine; dried over magnesium sulfate; and filtered. The
solution was purified by column chromatography on silica gel (eluting with 5% ethyl
acetate in dichloromethane) to provide 2.0 g of l-{[3-(4-fluorophenyl)isoxazol-5-
1 5 yljmethyl} -7V^bis(4-methoxybenzyl)-6,7-dimethyl- liy-imidazo[4,5-c]pyridin-4-amine as
a pale yellow solid.
PartF
A solution of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-AyV-bis(4--
methoxybenzyl)-6,7-dimethyl-l//-imidazo[4,5-c]pyridin-4 -amine (2.0 g, 3.5 mmol) in
20 trifluoroacetic acid (20 mL) was stirred at room temperature for 16 hours. The
trifluoroacetic acid was removed under reduced pressure, and the residue was triturated
with aqueous hydrochloric acid (25 mL of 6 N) and ethanol (20 mL) for 30 minutes. The
resulting mixture was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium
hydroxide and stirred at 0 °C for 30 minutes. A solid was present and was isolated by
25 filtration and purified by column chromatography on silica gel (eluting with 5% to 1 0%
CMA in chloroform). The resulting solid was dried under high vacuum at 100 °C for 18
hours to provide 0.708 g of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-
l#-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 244.0 - 246.0 °C.
MS(ESI)m/z338 (M + H)+;
30 Anal, calcd for Ci 8 Hi6FN 5 0: C, 64.09; H, 4.78; N, 20.76. Found: C, 63.40; H, 4.95; N,
20.76.
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Example 19
2-(Ethoxymethyl)-l - {[3^4-^
imidazo[4,5-c]pyridin-4-amine
F
Part A
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.4 g, 1 1 mmol) was added
dropwise to a solution of ^ 4 -{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-A^ 2 > A^ 2 -bis(4-
methoxybenzyO-S^-dimethylpyridine^^^-triamine (5.898 g, 10.39 mmol) and
triethylamine (2.2 mL, 15 mmol) in dichloromethane (30 mL) at 0 °C. After the reaction
was stirred for 0.7 hours, an analysis by HPLC indicated the presence of starting material,
and additional ethoxyacetyl chloride (0.54 g) was added. The stirring was continued, and
after 1.5 hours, the reaction mixture was diluted with dichloromethane and washed
sequentially with saturated aqueous potassium carbonate, water, and brine; dried over
sodium sulfate, filtered, and concentrated under reduced pressure to provide 6.2 g of 7V-[2-
[bis(4-methoxybenzyl)ammo]^
dimethylpyridin-3-yl]-2-ethoxyacetamide as a yellow oil.
PartB
The material from Part A, pyridine hydrochloride (1.1 g, 9.5 mmol), toluene (30
mL) were combined and heated at reflux for three days, allowed to cool to room
temperature, and concentrated under reduced pressure. The residue was dissolved in
dichloromethane, and the resulting solution was washed sequentially with aqueous
potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and
concentrated under reduced pressure. The resulting reddish-orange oil (6.94 g) was
purified by column chromatography on silica gel (240 g, eluting with 20% ethyl acetate in
hexane) to provide 3.55 g of 2-(ethoxymethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-AyV-bis(4-m^
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PartC
A solution of 2-(ethoxymethylH-{[3-(4-fluoropte
bis(4-methoxybenzyl)-6 J-dimethyl4iy-imidazo[4,5-c]pyridin"4-amine (3.55 g, 5.58
mmol) in trifluoroacetic acid (30 mL) was stirred at room temperature for three days. The
trifluoroacetic acid was removed under reduced pressure, and the residue was triturated
with hydrochloric acid (50 mL of a 6 N in ethanol) and water (1 0 mL) for 30 minutes.
The resulting mixture was adjusted to pH 14 with the addition of 50% (w/w) aqueous
sodium hydroxide and stirred for 30 minutes. The volatiles were removed under reduced
pressure, and the residue was recrystallized from aceotnitrile after a hot filtration. Three
crops of crystals were collected to provide 1.35 g of 2-(ethoxymethyl)-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}^ A
portion of this material was diluted with dichloromethane. The resulting solution was
washed sequentially with aqueous potassium carbonate, water, and brine; purified by
column chromatography on silica gel (250 g, eluting with 15% CMA in chloroform); and
dried to provide 0.657 g of an analytically pure sample as a white powder, mp 246.0 -
247.0 °C.
MS (ESI) m/z 396 (M + H)+;
Anal, calcd for C 2 iH 22 FN 5 02: C, 63.79; H, 5.61; N, 17.71. Found: C, 63.59; H, 5.50; N,
17.57.
Example 20
(4-Amino4-{[3-(4-fluorophenyl)isoxazo^
c]pyridin-2-yl)methanol
F
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-li/-imidazo[4,5-c]pyrid
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(0.8545 g, 2.161 mmol) in dichloromethane (50 mL) was cooled to about 6 °C, and boron
tribromide (5.4 mL of a 1 M solution in dichloromethane) was added dropwise. The
reaction was heated at reflux under nitrogen for two hours and diluted with
dichloromethane and methanol. The resulting solution was washed sequentially with
aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and
concentrated under reduced pressure. The resulting solid was stirred in water overnight,
isolated by filtration, purified by column chromatography on silica gel (eluting with 3% to
5% CMA in chloroform), and dried to provide 0.283 g of (4-amino-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}-6,7-^
yl)methanol as a tan powder, mp 164.0 - 165.0 °C.
MS (ESI) mfz 368 (M + H)+;
Anal, calcd for Ci9H 18 FN 5 0 2 : C, 62.12; H, 4.94; N, 19.06. Found: C, 61.80; H, 4.81; N,
18.94.
Example 21
2-Ethyl-l - { [3-(4-fluorophenyty^
c]pyridin-4-amine
F
Part A
TV 4 - {[3<4-Fluorophenyl)isoxazol-5-yl]methyl}-A^^ 2 -bis(4~methoxybenzyl)-5,6-
dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthopropionate (3.2 mL, 16
mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined
and treated according to the method described in Part E of Example 18 with the
modification that no additional triethyl orthopropionate was added. 2-Ethyl-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl} -7\^V : bis(4-methoxybenzyl)-6,7-dimethyl- 1H-
imidazo[4,5-c]pyridin-4-amine (2.52 g) was obtained as a yellow solid.
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PartB
Under a nitrogen atmosphere, a solution of 2-ethyl-l-{[3-(4-fluorophenyl)isoxazol-
S-ylJmetoylJ-iV^is^-memoxyte
(2.52 g, 4.16 mmol) in trifluoroacetic acid (25 g) was stirred at room temperature for 20
hours. The trifluoroacetic acid was removed under reduced pressure, and the resulting red
oil was stirred with aqueous hydrochloric acid (25 mL of 6 N) and ethanol (10 mL) for 30
minutes. The resulting mixture filtered to remove a solid impurity, cooled to 0 °C,
adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide, and stirred
at for 30 minutes. A solid was present and was isolated by filtration and purified by
sequential trituration with toluene, trituration with diethyl ether, and recrystallization from
acetonitrile to provide 0.6488 g of 2-ethyl-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-
6,7-dimemyl-liy-imidazo[4,5-c]pyridin-4-amine as a white flocculant solid, mp 255.0 -
256.0 °C.
MS (ESI) m/z 366 (M + H)+;
Anal, calcd for C 20 H 2 oFN 5 0: C, 65.74; H, 5.52; N, 19.17. Found: C, 65.62; H, 5.43; N,
19.14.
Example 22
l-{[3-(4-Fluorophenyl)isoxazol-5-yl]mefoyty
4-amine
NH,
F
Part A
A' 4 -{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-^ 2 ^V 2 -bis(4-methoxybenzyl)-5,6-
dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthoacetate (2.9 mL, 16
mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined
and treated according to the method described in Part E of Example 18 with the
modification that no additional triethyl orthoacetate was added. 1 - {[3-(4-
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Fluorophenyl)isoxazol-5-yl]m^
imidazo[4,5~c]pyridin-4-amine (1 .48 g) was obtained as a yellow solid.
PartB
Under a nitrogen atmosphere, a solution of l-{[3-(4-fluorophenyl)isoxazol-5-
5 yl]methyl}-A^-bis(4-meth^^
(1.48 g, 2.50 mmol) in trifluoroacetic acid (20 g) was stirred at room temperature for 24
hours. The solution was then worked-up and the product isolated as described in Part B of
Example 21 . After the desired product was collected by filtration, it was purified by
column chromatography on silica gel (60 g, eluting with 5% to 10% CMA in chloroform)
10 to provide 0.235 g of l-{[3<4-fluorophenyl)isoxazol-5-yl]methyl}-2,67-trimethyl-l//'-
imidazo[4,5~c]pyridin-4-amine as a white powder, mp 278.0 - 279.0 °C.
MS (ESI) m/z 352 (M + H)+;
Anal, calcd for Ci 9 Hi 8 FN 5 0: C, 64.95; H, 5.16; N, 19.93. Found: C, 64.78; H, 5.05; N,
20.12.
15
Example 23
1 - { [3 ~(4-Fluorophenyl)isoxazol-5-yl]methyl} -6,7-dimethyl-2-propyl- l#-imidazo[4,5 -
c]pyridin-4-amine
F
20 Part A
TV 4 - { [3 -(4-Fluorophenyl)isoxazol-5-yl]methyl}^
dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), trimethyl orthobutyrate (2.4 g, 16
mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined
and treated according to the method described in Part E of Example 18 with the
25 modification that no additional trimethyl orthobutyrate was added. l-{[3-(4-
Fluorophenyl)isoxazol-5-yl]methyl}-^^
l/Z-imidazo^jS-^pyridin^-amine (2.62 g) was obtained as a yellow solid.
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PartB
Under a nitrogen atmosphere, a solution of l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-N,AM)is(4-meta
4-amine (2.62 g, 4.23 mmol) in trifluoroacetic acid (25 mL) was stirred at room
temperature for 2.7 days. The solution was then worked-up and the product isolated and
purified as described in Part B of Example 21 to provide 0.549 g of l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}~6^^
amine as a white powder, mp 227.0 - 229.0 °C.
MS (ESI) m/z 380 (M + H)+;
Anal, calcd for C2iH 22 FN 5 0: C, 66.48; H, 5.84; N, 18.46. Found: C, 66.46; H, 5.65; N,
18.52.
Example 24
4-CMoro-l-{[3-(4-fluorophenyl)isoxazo^
CI
F
Part A
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride
(54 g, 230 mmol), prepared as described in Parts A through C of Example 1 1, was added
to a solution of 2-chloro-3-nitro-iV-prop-2-ynylquinolin-4-amine (30.2 g, 1 15 mmol),
prepared as described in Part A of Example 3, in dichloromethane (1 L) at room
temperature. Triethylamine (26 g, 250 mmol) was added; a precipitate formed. The
resulting mixture was heated at 40 °C under nitrogen for 16.5 hours and concentrated
under reduced pressure. The resulting solid was dissolved in ethyl acetate, and the work-
up and isolation procedures described in Part B of Example 18 were followed to provide
36. 1 2 g of 2-chloro-N- { [3-(4-fluorophenyl)isoxazol-5-yl]methyl} -3-nitroquinolin-4-amine
as a yellow solid.
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PartB
Under a nitrogen atmosphere, acetonitrile (2 L) was added to a Parr vessel
containing 5% platinum on carbon (2.0 g) and 2-chloro-7/-{[3-(4-fIuorophenyl)isoxazol-5-
yl]methyl}-3-nitroquinolin-4-amine (36.12 g, 90.58 mmol). The vessel was sealed,
5 purged with nitrogen, and placed under hydrogen pressure (30 psi, 2.1 x 10 5 Pa) for 17
hours at room temperature. The catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. The resulting semi-solid was treated with diethyl
ether, which was removed under reduced pressure to provide 33 g of 2-chloro-7V 4 -{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}quinoUne-3,4-diamine as a yellow-orange solid. A
1 0 portion of the material was purified by column chromatography on silica gel (6 g, eluting
with 10% ethyl acetate in hexane) to provide 0.0298 g of an analytically pure sample as
pale yellow crystals, mp 127 - 128.0 °C.
MS (EST) m/z 369 (M + H)+;
Anal, calcd for C 19 Hi 4 ClFN 4 0: C, 61.88; H, 3.83; N, 15.19. Found: C, 61.67; H, 3.88; N,
15 15.14.
The reaction mixture from a separate reduction carried out in toluene was filtered
to remove the catalyst, and the filtrate was used in the next step.
PartC
Pyridine hydrochloride (3 mg, 0.02 mmol) and triethyl orthoformate (0.3 mL, 1.7
20 mmol) were added to a solution of 2-chloro-iV 4 - {[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}quinoline-3,4-diamine (0.4294 g, 1.164 mmol) in toluene (10 mL), and the
reaction was heated at 1 10 °C for 16 hours. A solid was present and was isolated by
filtration. The filtrate was concentrated under reduced pressure and triturated with diethyl
ether to provide a solid. The two solids were combined and purified by column
25 chromatography on silica gel (eluting with 1 :1 ethyl acetate:hexane) to provide 0.259 g of
4-chloro-l- {[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l//-imidazo[4,5-c]quinoline as a
white solid, mp 219.0 - 220.0 °C.
MS (ESI) m/z 379 (M + H)+;
Anal, calcd for C 2 oH 12 ClFN 4 0: C, 63.42; H, 3.19; N, 14.79. Found: C, 63.49; H, 2.83; N,
30 14.73.
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Example 25
l-{[3-(4-Fluorophenyl)isoxa
F
A mixture of 4-cWoro-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-lff-
imidazo[4,5-c]quinoline (0.2322 g, 0.6130 mmol) and 7 N ammonia in methanol (10 mL)
was sealed in a pressure vessel and heated at 150 °C for 22 hours and allowed to cool to
room temperature. The volatiles were removed under reduced pressure, and the resulting
orange solid was triturated with diethyl ether. The solid was then purified by column
chromatography on silica gel (7 g, eluting with 10% to 20% CMA in chloroform),
triturated with diethyl ether, isolated by filtration, and dried. The solid was then boiled in
methanol in the presence of a small amount of 0.5 N sodium hydroxide in methanol. The
mixture was allowed to cool to room temperature, and the solid was isolated by filtration
and dried to provide 0.0259 g of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-liy-
imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 259.0 - 260.0 °C.
MS (ESI) m/z 360 (M + H)+;
Anal, calcd for C2oH 14 FN 5 00.5 H 2 0: C, 65.21; H, 4.10; N, 19.01. Found: C, 64.90; H,
3.87; N, 18.81.
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Example 26
2-Ethyl-l - {[3-(4-fluoro^^
F
Part A
5 Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0. 1 9 mmol),
triethyl orthopropionate (2.5 g, 14 mmol), 2-chloro»7V 4 -{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined
and heated at 110 °C for 18 hours. Most of the volatiles were removed under reduced
pressure to provide a suspension. The solid was isolated by filtration, washed with diethyl
10 ether, and dried to provide 2.624 g of 4-chloro-2-ethyl-l - {[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-li^imidazo[4 3 5-c]quinoline as a tan solid.
PartB
4-Chloro-2-ethyl- 1 - { [3-(4-fluorophenyl)isoxazol-5 -yl]methyl} - l#-imidazo[4,5-
cjquinoline (2.624 g, 6.451 mmol), 7 N ammonia in methanol (40 mL), and
15 tetrakis(triphenylphosphine)palladium(0) were combined in a pressure vessel and heated at
120 °C for 16 hours. An analysis by HPLC indicated that the reaction was incomplete.
The volatiles were removed under reduced pressure, and the residue was dissolved in
chloroform. The solution was washed sequentially with aqueous potassium carbonate,
water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced
20 pressure. The resulting dark yellow solid was added to a pressure vessel with 7 N
ammonia in methanol (60 mL), and the reaction was sealed and heated at 150 °C for 18
hours. The volatiles were removed under reduced pressure, and the residue was stirred
with 0.5 N potassium hydroxide m methanol for 30 minutes. The resulting solid was
isolated by filtration, diluted with dichloromethane, purified by column chromatography
25 on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether
and filtered, and recrystallized from acetonitrile after a hot filtration. The crystals were
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isolated by filtration, washed with diethyl ether, and dried to provide 0.139 g of 2-ethyl-l-
{[3-(4-fluorophenyl)isoxazol-5-yl]me^ as a white
powder, mp 232.0 - 233.0 °C.
MS (ESI) m/z 388 (M + H)+;
Anal, calcd for C 2 2Hi 8 FN 5 0: C, 68.21; H, 4.68; N, 18.08. Found: C, 68.16; H, 4.29; N,
18.19.
Example 27
l-{[3-(4-Fluorophenyl)isoxazol-5-yl]me%^
amine
F
Part A
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol),
trimethyl orthobutyrate (2.1 g, 14 mmol), 2-chloro-iV 4 -{[3-(4-fluorophenyl)isoxa2ol-5-
yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined
and heated at 1 10 °C for 18 hours. The volatiles were removed under reduced pressure.
The crude product was purified by column chromatography on silica gel (250 g, eluting
with 20% to 40% ethyl acetate in hexane) to provide 0.806 g of 4-chloro-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-l^-imidazo[4,5-c]quinoline as a yellow
solid.
PartB
A mixture of 4-chloro- 1 - { [3-(4-fluorophenyl)isoxazol-5-yl]methyl} -2-propyl- IH-
imidazo[4,5-c]quinoline (0.806 g, 1.92 mmol) and 7 N ammonia in methanol (40 mL) was
sealed in a pressure vessel and heated at 150 °C for 18 hours and allowed to cool to room
temperature. The volatiles were removed under reduced pressure, and the resulting solid
was stirred with 0.5 N sodium hydroxide in methanol. The solid was isolated by filtration,
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washed with diethyl ether, purified by column chromatography on silica gel (eluting with
5% to 10% CMA in chloroform), triturated with diethyl ether, isolated by filtration, and
dried to provide 0.123 g of l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-li/-
imidazo[4,5-c]quinolin-4-amine as a white powder, mp 226.0 - 227.0 °C.
5 MS(ESI)m/z401(M + H)+;
Anal, calcd for C23H20EN5O: C, 68.81; H, 5.02; N, 17.45. Found: C, 68.67; H, 4.92; N,
17.53.
Example 28
10 1 - { [3-(4-Fluorophenyl)isoxazol-5-yl]methyl} -2 -methyl- li/-imidazo[4,5-c]quinolin-4-
amine
F
Part A
Pyridine hydrochloride (0.020 g, 0.19 mmol), triethyl orthoacetate (2.3 g, 14
15 mmol), 2-cWoro-7V 4 -{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamm (3.5
g, 9.5 mmol), and toluene (50 mL) were combined and treated according to the method of
Part A of Example 26 to provide 2.307 g of 4-chloro-l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-2-methyl-l//-imidazo[4,5-c]quinoline as a pale yellow solid.
PartB
20 4-CMoro4-{[3-(4-fluorophenyl)isox
c]quinoline (2.307 g, 5.873 mmol) was treated according to the method described in Part B
of Example 27 using 60 mL of 7 N ammonia in methanol. Following the purification
steps, the solid product was stirred for 16 hours in 25% potassium hydroxide in ethanol,
isolated by filtration, washed with water and isopropyl alcohol, and dried. The resulting
25 white solid was stirred for one hour with 6 N hydrogen chloride in ethanol, and the
mixture was then adjusted to pH 14 with the addition of 6 N potassium hydroxide. The
solid was isolated by filtration, washed with water and diethyl ether, and dried under high
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vacuum at 100 °C for 18 hours to provide l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2.
methyl- li7-imidazo[4,5-c]quinolin^-ainine as a white powder, mp 294.0 - 296.0 °C.
MS (ESI) m/z 374 (M + H)+;
Anal, calcd for C 2 iH 16 FN 5 0: C, 67.55; H, 4.32; N, 18.76. Found: C, 67.50; H, 4.28; N,
18.97.
Example 29
4-CMoro-2-(etaymethyl)-l-{^
c]quinoline
Under a nitrogen atmosphere, ethoxyacetyl chloride (5.5 g, 45 mmol) was added
dropwise to a solution of 2-chloro-A^-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}quinoline-3,4-diamine (15.00 g, 40.67 mmol) and triethylamine (8.5 mL, 61
mmol) in dichloromethane (200 mL) at 6 °C. After the reaction was stirred for 30
minutes, an analysis by HPLC indicated the presence of starting material, and additional
ethoxyacetyl chloride (1.01 g) was added. The stirring was continued, and over the course
of five hours, a total of 13 g of ethoxyacetyl chloride was added. The work-up procedure
described in Part A of Example 19 was followed to provide iV-[2-chloro-4-({[3-(4-
fluorophenyl)isoxazol-5-yl]methyl}amino)quinolin-3-yl]-2-ethoxyacetamide as an orange
solid.
PartB
The material from Part A, pyridine hydrochloride (2.0 g, 2.0 mmol), toluene (500
mL) were combined under a nitrogen atmosphere and heated at 1 10 °C for 22 hours,
allowed to cool to room temperature, and concentrated under reduced pressure. The
residue was partitioned between dichloromethane and saturated aqueous potassium
Cl
F
Part A
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carbonate. The aqueous layer was separated and extracted with dichloromethane. The
combined organic fractions were washed sequentially with water and brine, dried over
magnesium sulfate, and filtered. The volume was reduced to 20 mL by concentration
under reduced pressure, and a precipitate formed. The precipitate was isolated by
filtration, washed with toluene and diethyl ether, and dried under vacuum to provide 12.6
g of 4-chloro-2-(ethoxymethyl)-l- {[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l^-
imidazo[4,5-c]quinoline. A portion of the product was recrystallized from methanol to
provide 0.509 g of an analytically pure sample as tan crystals, mp 189.0 - 190.0 °C.
MS (ESI) m/z 437 (M + H)+;
Anal, calcd for C23H18CIFN4O2: C, 63.23; H, 4.15; N, 12.82. Found: C, 63.16; H, 4.16; N,
12.81.
Example 30
2-(Ethoxymethyl)-l-{[3-(4-fl^
c]quinolin-4-amine
F
A mixture of 4-chloro-2-(ethoxymethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-
yl]methyl}-l//-imidazo[4,5-c]quinoline (3.00 g, 6.87 mmol) and 7 N ammonia in
methanol (150 mL) was sealed in a pressure vessel and heated at 150 °C for 18 hours and
allowed to cool to room temperature. A precipitate formed and was isolated by filtration,
washed with diethyl ether, and dried to provide 1.858 g of product. Half of the material
was further dried for three days at 100 °C under high vacuum to provide 0.816 g of 2-
(ethoxyme%l)4-{[3-(4-fiuoroph^
4-amine as a white, crystalline solid, mp 203.0 - 204.0 °C.
MS (ESI) m/z 41 8 (M + H)+;
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10
15
20
Anal, calcd for C23H20FN5O2: C, 66.18; H, 4.83; N, 16.78. Found: C, 66.02; H, 4.67; N,
16.97.
Example 31
(4-Amino-l - {[3-(4-fluorophen^
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-l-{[3-(4-
fluorophenyl)isoxazol-5-yl]me^ (0.9923 g, 2.377
mmol) in 1,2-dichloroethane (55 mL) was cooled to about 0 °C, and boron tribromide (5.9
tnL of a 1 M solution in dichloromethane) was added dropwise. After the reaction was
stirred cold for 30 minutes, it was heated at 50 °C for six hours. An analysis by HPLC
indicated the reaction was incomplete, and the reaction was again cooled to about 0 °C,
and additional boron tribromide (1.5 mL) was added dropwise. After the reaction was
stirred cold for ten minutes, it was heated at 50 °C for 16 hours. Methanol (30 mL) was
added, and the reaction mixture was allowed to cool to room temperature. After 16 hours,
the precipitate from the reaction was isolated by filtration and washed sequentially with
aqueous potassium hydroxide (30 mL of 1 N), methanol (15 mL), and diethyl ether (15
mL). The solid was then triturated with boiling acetonitrile and isolated by hot filtration to
provide 0.161 g of (4-amino-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l//-
imidazo[4,5-c]quinolin-2-yl)methanol as a white powder, mp 262.0 - 263.0 °C.
MS (ESI) m/z 390 (M + H)+;
Anal, calcd for C 2 iH 16 FN 5 0 2 : C, 64.78; H, 4.14; N, 17.99. Found: C, 64.53; H, 3.87; N,
18.11.
yl)methanol
NH.
F
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Example 32
2-(FluoromethylH-{[3^
c]quinolin-4- amine
F
The methods described in Examples 30 and 31 were repeated on a larger scale to
provide (4-amino-l-{[3-(4-fluo^
c]quinolin-2-yl)methanol. The reaction described in Example 31 was heated at reflux and
was complete within three hours. Under a nitrogen atmosphere, a suspension of (4-amino-
1 - { [3<4-fluorophenyl)isoxazol-5-yy
(2.31 g, 5.93 mmol) in dichloromethane (100 mL) was cooled to -78 °C.
(Diethylamino)sulfur trifluoride (DAST) (0.95 mL, 7.2 mmol) was added dropwise. The
mixture was stirred for 30 minutes at -78 °C and then was allowed to warm to room
temperature slowly and stirred for one hour. The reaction mixture was diluted with
dichloromethane and washed with saturated aqueous potassium carbonate. Additional
dichloromethane and water were added to dissolve solids. The aqueous layer was
separated and extracted with dichloromethane. The combined organic fractions were
washed sequentially with water and brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (eluting with 3% to 5% CMA in chloroform) followed by
recrystallization from acetonitrile. The crystals were dried under high vacuum for 1 8
hours at 90 °C to provide 0.994 g of 2-(fluoromethyl)-l.{[3-(4-fluorophenyl)isoxazol--5~
yl]me%l}-l/f-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 192.0 - 193.0 °C.
MS (ESI) m/z 392 (M + H)+;
Anal, calcd for C2iHi 5 F 2 N 5 0: C, 64.45; H, 3.86; N, 17.89. Found: C, 64.39; H, 3.72; N,
17.93.
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10
15
20
Example 33
2-(Ethoxymethyl)- 1 - {2^
c]quinolin-4-amine
Under a nitrogen atmosphere, 4-fluoro-iV-hydroxybenzenecarboximidoyl chloride
(31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added
dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and JV-(3-
butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was
stirred at room temperature for 24 hours and then diluted with dichloromethane, washed
sequentially with aqueous potassium carbonate, water, and brine; dried over potassium
sulfate; filtered; and concentrated under reduced pressure. The resulting solid was
triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide
29.87 g of 2-{2^3-(4-fluorophenyl)isoxazol-5-yl^ A
portion of the product was recrystallized from isopropyl alcohol and dried to provide an
analytically pure sample as white crystals, mp 155.0 - 156.0 °C.
MS (ESI) m/z 337 (M + H)+;
Anal, calcd for C19H13FN2O3: C, 67.85; H, 3.90; N, 8.33. Found: C, 67.88; H, 3.86; N,
8.33.
PartB
A mixture of 2- {2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-l^-isoindole-l ,3(2fif)-
dione (27.14 g, 80.70 mmol), hydrazine hydrate (9.8 mL, 202 mmol), and ethanol (700
mL) was heated at reflux under nitrogen for two hours. The reaction mixture was filtered
to remove a solid, and the filtrate was concentrated under reduced pressure. The resulting
oil was dissolved in ethyl acetate, and the solution was washed sequentially with water and
Part A
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brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to
provide 16.14 g of 2-[3-(4-fluorophenyl)isoxazol-5-yl]ethylamine as a colorless oil
PartC
Under a nitrogen atmosphere, triethylamine (14.9 mL, 107 mmoL) was added to a
solution of 2,4-dichloro-3-nitroquinoline (17.29 g, 71.15 mol) in anhydrous l-methyl-2-
pyrrolidinone (NMP) (100 mL). The mixture was stirred until it was homogeneous and
then was cooled to 6 °C. 2-[3-(4-Fluorophenyl)isoxazol-5-yl]ethylamine (14.9 mL, 107
mmol) was added dropwise over a period of 30 minutes; the temperature did not rise
above 10 °C during the addition. After the reaction was stirred for 1 .75 hours, deionized
water (100 mL) was added. A precipitate formed, and the mixture was stirred for 30
minutes. The precipitate was isolated by filtration, and washed with deionized water until
the filtrate was pH 8. The filter cake was then washed sequentially with toluene (100 mL)
and a small amount of diethyl ether and dried for 18 hours to provide 27.84 g of 2-chloro-
A^{243-(4-fluorophenyl)isoxazol-5-yl]e%l}-3-nitroqumolin--4-amine as a bright yellow
solid.
PartD
Under a nitrogen atmosphere, acetonitrile (1 .5 L) was added to a Parr vessel
containing 5% platinum on carbon (1.5 g), which had been wet with a small amount of
acetonitrile, and 2-cMoro-AT-{2-[3-(4-fluoropheny^
amine (23.20 g, 56.20 mmol). The vessel was sealed, purged three times with hydrogen,
and placed under hydrogen pressure (30 psi, 2.1 x 10 5 Pa) for 18 hours at room
temperature. The catalyst was removed by filtration, and the majority of the filtrate was
concentrated under reduced pressure. A solid was present in the remaining filtrate and
was isolated by filtration to provide 1 1.3 g of 2-chloro-7V 4 -{2-[3-(4-fluorophenyl)isoxazol-
5-yl]ethyl} quinoline-3,4-diamine as a yellow solid.
PartE
Under a nitrogen atmosphere, ethoxyacetyl chloride (3.5 g, 28 mmol) was added
dropwise to a solution of 2-chloro-iV 4 -{2-[3-(4-fluorophenyl)isoxazol-5-
yl]ethyl}quinoline-3,4-diamine (9.0 g, 23.5 mmol) and anhydrous triethylamine (10.0 mL,
35.3 mmol) in anhydrous dichloromethane (75 mL) at 6 °C. After the reaction was stirred
for 30 minutes, an analysis by HPLC indicated the presence of starting material, and
additional ethoxyacetyl chloride (2.0 g) was added. After the reaction was stirred for
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another 30 minutes, it was still incomplete, and additional ethoxyacetyl chloride (2.0 g)
was added. The stirring was continued for an additional 30 minutes, and the work-up
procedure described in Part A of Example 1 9 was followed to provide 1 1 . 1 2 g of ^-[2-
cMoro-4-({2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}amino)quinolin-3-yl]-2-
ethoxyacetamide as a white solid.
PartF
A mixture of ^-[2-chloro-4-({2-[3-(4-fluorophenyl)isoxazol-5-
yl]ethyl}amino)quinolin-3-yl]-2-ethoxyacetamide (0.500 g, 1.07 mmol) and 7 N ammonia
in methanol (7 mL) was sealed in a pressure vessel and heated at 150 °C for 12 hours and
allowed to cool to room temperature. The reaction mixture was diluted in
dichloromethane, and the resulting solution was washed sequentially with aqueous
potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and purified by
column chromatography on silica gel (40 g, eluting with 5% to 10% CMA in chloroform).
The product was then recrystallized from toluene (20 mL), and the crystals were isolated
by filtration, washed with toluene, and dried provide 0.139 g of 2-(ethoxymethyl)-l-{2-[3-
(4-fluorophenyl)isoxazol-5-yl]ethyl}-l//-imidazo[4,5-c]quinolin-4-amine as a white
powder, mp 180.0 - 181.0 °C. MS (ESI) m/z 432 (M + H)+;
Anal, calcd for C24H22FN5O2: C, 66.81; H, 5.14; N, 16.23. Found: C, 66.56; H, 5.15; N,
16.01.
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Example 34
1- {243-(4-Fluoropheny^
amine
NH 0
F
5 Part A
Under a nitrogen atmosphere, pyridine hydrochloride (1.6 g, 14 mmol), trimethyl
orthobutyrate (1.62 g, 11.0 mmol), 2-chloro-7V 4 -{2-[3-(4-fluorophenyl)isoxazol-5-
yl]ethyI}quinoline-3,4-diamine (2.10 g, 5.49 mmol), and toluene (50 mL) were combined
and heated at reflux for four hours under a Dean-Stark trap. The volatiles were removed
10 under reduced pressure. The resulting oil was dissolved in ethyl acetate, and the solution
was washed sequentially with aqueous potassium carbonate, water, and brine; dried over
sodium sulfate; filtered; and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (eluting with 4:6 hexane:ethyl acetate) to
provide 1.22 g of 4-chloro-l-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-lH-
15 imidazo[4,5-c]quinoline as a pale yellow solid.
PartB
A mixture of 4-chloro-l-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-l//-
imidazo[4,5-c]quinoline (1.22 g, 2.81 mmol) and 7 N ammonia in methanol (100 mL) was
sealed in a pressure vessel and heated at 150 °C for 12 hours and allowed to cool to room
20 temperature. The volatiles were removed under reduced pressure, and the crude product
was purified by column chromatography on silica gel (eluting with 10% to 15% CMA in
chloroform). The product was then triturated sequentially with toluene and hexane/diethyl
ether to provide 0.312 g of l-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-liy-
imidazo[4,5-c]quinolin-4-amine as a white powder, mp 208.0 - 209.0 °C.
25 HRMS (ESI) calcd for C24H22FN5O: 416.1887, found: 416.1909;
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10
15
20
Anal, calcd for C24H22FN5O: C, 69.38; H, 5.34; N, 16.86. Found: C, 69.19; H, 5.27; N,
16.84.
Example 35
l-[(5-Butylisoxazol-3-yl)methyl]-l^
NhL
Water (50 mL) and trifluoroacetic acid (50 mL) were added to a solution of
phthalimidoacetaldehyde diethyl acetal (30.0 g, 1 14 mmol) in chloroform (200 mL), and
the reaction mixture was stirred at room temperature for 48 hours. The aqueous layer was
separated, adjusted to pH 7 with the addition of sodium carbonate, and extracted with
several portions of dichloromethane. The combined organic fractions were dried over
magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.2 g of
(l,3-dioxo-l,3-dihydro-2^~isoindol-2-yl)acetaldehyde as a white solid.
PartB
Hydroxylamine hydrochloride (5.74 g, 82.6 mmol) and triethylamine (31.4 mL,
225 mmol) were sequentially added to a solution of (l,3-dioxo-l,3-dihydro-2^/-isoindol-2-
yl)acetaldehyde (14.2 g, 75.1 mmol) in dichloromethane. The resultant suspension was
stirred at room temperature for several hours and adjusted to pH 6 with the addition of
saturated aqueous ammonium chloride. The aqueous layer was then separated and
extracted with several portions of dichloromethane. The combined organic fractions were
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on a vacuum filter funnel (silica gel, eluting with
3% to 5% methanol in dichloromethane). The product was then dissolved in
dichloromethane, and the solution was washed with 1 N hydrochloric acid. The aqueous
layer was extracted a few times with dichloromethane, and the combined organic fractions
were dried over magnesium sulfate, filtered, and concentrated to provide 13.05 g of (1,3-
dioxo-l,3-dihydro-2#-isoindol-2-yl)ethanal oxime as a white solid.
Part A
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PartC
iV-Chlorosuccinimide (8.50 g, 63.7 mmol) was added to a solution of (1,3-dioxo-
l,3-dihydro-2#-isoindol-2-yl)ethanal oxime (13.0 g, 63.7 mmol) in DMF (100 mL), and
the solution was heated at 50 °C gently for two hours and allowed to cool to room
temperature. The solution was diluted with ethyl acetate and washed three times with
water and once with brine, dried over magnesium sulfate, filtered, and concentrated to
provide 15.0 g of 2-(l,3-dioxo4,3-dihydro-2^-isoindol-2-yl)-^-hydroxyethaiiimidoy^
chloride as a pale yellow solid.
PartD
1-Hexyne (5.16 g, 62.9 mmol) and triethylamine (6.36 g, 62.9 mmol) were
sequentially added to a suspension of 2-(l,3-dioxo-l,3-dihydro-2//-isoindol-2-yl)-A r -
hydroxyethanimidoyl chloride (5.0 g, 21 mmol) in chloroform (80 mL). The solution was
stirred overnight at room temperature, washed sequentially with 0.5 M hydrochloric acid
and brine, dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column chromatography on silica gel
(eluting with 3:1 to 1:1 hexane.ethyl acetate) to provide 2.14 g of 2-[(5-butylisoxazol-3-
yl)methyl]-l J H r -isoindole-l,3(2//)-dione as a white, crystalline solid.
PartE
A solution of hydrazine hydrate (888 mg, 15.1 mmol) in THF (5 mL) was added to
a solution of 2-[(5-butylisoxazol-3-yl)methyl]-li/-isoindole-l,3(2//)-dione (2.14 g, 7.53
mmol) in 2: 1 ethanol:THF (60 mL), and the solution was heated at reflux gently for four
hours. A precipitate formed and was removed by filtration and washed with THF. The
filtrate was concentrated under reduced pressure to provide 1.0 g of (5-butylisoxazol-3-
yl)methylamine as a pale yellow solid.
PartF
4-Chloro-3-mtroquinoline (1.35 g, 6.48 mmol) and triethylamine (1.36 mL, 9.73
mmol) were sequentially added to a solution of (5-butylisoxazol-3-yl)metiiylamine (1.00
g, 6.48 mmol) in dichloromethane, and the solution was stirred for 48 hours at room
temperature. The volatiles were removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (eluting with 3% methanol in
dichloromethane) to provide 1.33 g of JV-[(5-butylisoxazol-3-yl)methyl]-3-nitroquinolin-4-
amine as a yellow, crystalline solid.
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PartG
Catalytic 5% platinum on carbon (150 mg) was added to a suspension of i\T-[(5-
butylisoxazol-3-yl)methyl]-3-nitroquinolin-4-amine (1.33 g, 4.08 mmol) in acetonitrile (50
mL), and the mixture was placed under hydrogen pressure (40 psi, 2.8 x 10 5 Pa) for six
hours. The mixture was filtered through a layer of CELITE filter agent, and the filtrate
was concentrated under reduced pressure to provide 1.19 g of A^~[(5-butylisoxazol-3-
yl)methyl]quinoline-3,4-diamine.
PartH
Triethyl orthoformate (0.80 mL, 4.80 mmol) and pyridine hydrochloride (0.092 g,
0.80 mmol) were sequentially added to a solution of ^-[(S-butylisoxazol-S-
yl)methyl]quinoline-3,4-chamine (1.19 g, 4.00 mmol) in acetonitrile (100 mL), and the
solution was heated gently at reflux overnight. An analysis by HPLC indicated the
presence of starting material, and additional triethyl orthoformate and pyridine
hydrochloride were added. The solution was heated at reflux for an additional 24 hours.
The solvents were removed under reduced pressure, and the residue was partitioned
between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer
was separated and extracted with dichloromethane, and the combined organic fractions
were washed with brine, dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by flash column chromatography on
silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 1.06 g of l-[(5-
butylisoxazol-3-yl)methyl]-l//-imidazo[4,5-c]quinoline as an orange solid.
Parti
mCPBA (930 mg of 77% pure material, 4.2 mmol) was added to a solution of 1-
[(5-butyUsoxazol-3-yl)methyl]4i^imidazo[4,5-c]quinoline (L06 g, 3.46 mmol) in
chloroform (40 mL), and the solution was stirred for 1.5 hours at room temperature. /?-
Toluenesulfonyl chloride (726 g, 3.81 mmol) and concentrated ammonium hydroxide (15
mL) were then added, and the mixture was stirred vigorously for three hours at room
temperature. Saturated aqueous sodium bicarbonate was added, and the aqueous layer was
separated and extracted several times with chloroform. The combined organic fractions
were washed with brine, dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The resulting orange solid was purified by flash column
chromatography on silica gel (eluting with 4% to 8% methanol in dichloromethane) to
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provide 0.92 g of l-[(5-butylisoxazol-3-yl)methyl]-l^ as
a tan crystalline solid, mp 201-203 °C.
! H NMR (300 MHz, 4-DMSO) 5 8.28 (s, 1H), 7.88 (d, J= 8.1 Hz, 1H), 7.42 (m, 2H),
7.15 (t, 8.2 Hz, 1H), 6.75 (br s, 2H), 6.19 (s, 1H), 5.93 (s, 2H), 2.71-2.65 (m, 2H),
1.55-1.49 (m, 2H), 1.28-1.21 (m, 2H), 0.83 (t, 7- 7.3 Hz, 3H); HRMS (ESI) calcd for
Ci 8 H 19 N 5 0: 322.1668; found: 322.1684.
Example 36
2-Propyl-l-[(5-pyridin-3-ylisoxazol-3^^
Part A
The method described in Part D of Example 35 was followed using 3-
ethynylpyridine (3.24 g, 31.4 mmol) instead of 1-hexyne with the modification that the
eluent used for chromatographic purification was a gradient of 3:1 hexane:ethyl acetate to
100% ethyl acetate to 9:1 ethyl acetate:dichloromethane. 2-[(5-Pyridin-3-ylisoxazol-3-
yl)methyl]-l^T-isoindole-l J 3(2JT)-dione (2.95 g) was obtained as a yellow solid.
PartB
2-[(5-Pyridin-3-ylisoxazol-3-yl)methyl]-l//-isoindole-l,3(2i7)-dione (2.95 g, 9.67
mmol) was treated with hydrazine hydrate (1.14 g, 19.3 mmol) according to the method
described in Part E of Example 35 to provide (5-pyridin-3-yUsoxazol-3-yl)methylamine as
a pale yellow solid.
PartC
4-Chloro-3-nitroquinoline (2.09 g, 9.99 mmol) and triethylamine (2.10 mL, 15.0
mmol) were sequentially added to a solution of (5-pyridin-3-ylisoxazol-3-yl)methylamine
(2.09 g, 9.99 mmol) in dichloromethane, and the solution was stirred overnight at room
temperature. The resultant red solution was washed sequentially with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated
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under reduced pressure. The residue was purified by flash column chromatography on
silica gel (eluting with 2% to 5% methanol in dichloromethane) to provide 1.17 g of 3-
nitxo-7V L [(5-pyridin-3-ylisoxazol-3-yl)methyl]quinolin-4-amine as a yellow-orange solid.
PartD
3-Nitro-A4(5-pyridin-3^ (1.17 g, 3.37
mmol) was hydrogenated in the presence of 5% platinum on carbon (0.120 g) according to
the method described in Part G of Example 35 to provide 0.96 g of A^-[(5-pyridin-3-
ylisoxazol-3-yl)methyl]quinoline-3,4-diamine.
PartE
The methods of Part H of Example 35 were used to treat A^-[(5-pyridin-3-
ylisoxazol-3-yl)methyl]quinoline-3 5 4-diamine (0.95 g, 2.98 mmol) with trimethy
orthobutyrate (0.57 mL, 3.6 mmol) and pyridine hydrochloride (0.069 g, 0.60 mmol) and
purify the product to provide 0.930 g of 2-propyl-l-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-
l#-imidazo[4,5-c]quinoline as a tan solid.
PartF
The methods described in Part I of Example 35 were used to treat 2-propyl-l-[(5-
pyridin-3-ylisoxazol-3~yl)methy^ (0.920 g, 3.00 mmol) with
mCPBA (0.808 g of 77% pure material, 3.6 mmol) followed by /?-toluenesulfonyl chloride
(0.629 g, 3.30 mmol) and concentrated ammonium hydroxide (15 mL) and purify the final
product to provide 0.46 g of 2-propyM-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-l//-
imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 206-207 °C.
! H NMR (300 MHz, rf 6 -DMSO) 5 9.06 (d, J= 2.2 Hz, 1H), 8.66 (m, 1H), 8.23 (d, J= 8.0
Hz, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.65-7.25 (m, 3H), 7.16-7.12 (m, 2H), 6.55 (br s, 2H),
5.98 (s, 2H), 2.93 (t, / = 7.4 Hz, 2H), 1.86-1.81 (m, 2H), 1.02 (t, /= 7.2 Hz, 3H);
HRMS (ESI) calcd for C 2 2H 2 iN 6 0: 385.1777; found: 385.1781.
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Example 37
2-(Ethoxymethyl)-H(5-phenyhsoxazol-3-yl)mefo^
Part A
5 The methods described in Part D of Example 35 were followed using
phenylacetylene (5.35 g, 52.4 mmol) instead of 1-hexyne to provide 3.50 g of 2-[(5-
phenylisoxazol-3-yl)methyl]-lii/-isoindole-l 5 3(2/f)-dione as a pale yellow, crystalline
solid.
PartB
10 2-[(5-Phenylisoxazol-3-yl)methyl]4i/-isoindole-l,3(2 J fiO-dione (3.48 g, 1 1.4
mmol) was treated with hydrazine hydrate (1 .35 g, 22.9 mmol) according to the method
described in Part E of Example 35 to provide (5-phenylisoxazol-3-yl)methylamine as a
pale yellow solid.
PartC
1 5 A suspension of 4-chloro-3-nitroquinoline (2.29 g, 1 1.0 mmol) and (5-
phenylisoxazol-3-yl)methylamine (1.92 g, 1 1.0 mmol) in dichloromethane (200 mL) was
cooled to 0 °C, and triethylamine (2.30 mL, 16.5 mmol) was added. The resultant solution
was allowed to warm to room temperature slowly and stirred overnight. The volatiles
were removed under reduced pressure, and the residue was purified by flash column
20 chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to
provide 2.90 g of 3-nitroW-[(5-phenylisoxazol-3-yl)methyl]quinolin-4-aniine.
PartD
3-Nitro-7\^[(5-phenyUsoxazol-3-yl)methyl]quinolin-4-amine (2.90 g, 8.37 mmol)
was hydrogenated in the presence of 5% platinum on carbon according to the method
25 described in Part G of Example 35 to provide 2.06 g of ^-[(S-phenylisoxazol-S-
yl)methyl]quinoline-3,4-diamine.
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PartE
A solution of ethoxyacetyl chloride (0.87 g, 7.1 mmol) in acetonitrile (10 mL) was
added to a solution of A^-[(5-phenylisoxazol-3-yl)methyl]quinoline-3,4-diamine (2.05 g,
6.48 mmol) in acetonitrile (100 mL), and the solution was stirred at room temperature
5 overnight. The volatiles were removed under reduced pressure, and the residue was
dissolved in 3:1 ethanolrwater (100 mL). Solid sodium hydroxide (389 mg, 9.72 mmol)
was added, and the solution was heated at reflux overnight. The ethanol was removed
under reduced pressure, and the resultant aqueous solution was adjusted to pH 5 with the
additional of dilute hydrochloric acid. The acidic solution was extracted several times
10 with dichloromethane, and the combined organic fractions were washed with brine, dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel (eluting with 4% to
6% methanol in dichloromethane to provide 0.650 g of 2-(ethoxymethyl)-l-[(5-
phenylisoxazol-3-yl)mel!iyl]-li/-imida2;o[4,5-c]qxiinoline as a white solid.
15 PartF
The methods described in Part I of Example 35 were used to treat 2-
(ethoxymethyl)-l-[(5-phenyhsoxazo^ (0.650 g,
1.69 mmol) with mCPBA (0.455 g of 77% pure material, 2.0 mmol) followed by p-
toluenesulfonyl chloride (0.355 g, 1.86 mmol) and concentrated ammonium hydroxide (15
20 mL) and purify the final product to provide 0.3 8 g of 2-(ethoxymethyl)- 1 -[(5-
phenylisoxazol-3-yl)methyl]-l^-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid,
mp 221-223 °C.
*H NMR (300 MHz, tf 6 -DMSO) S 8.01 (d, J= 7.4 Hz, 1H), 7.80 (m, 2H), 7.60 (d, J= 7.4
Hz, 1H), 7.49 (m, 3H), 7.44 (t, /= 8.2 Hz, 1H), 7.15 (t, J= 8.2 Hz, 1H), 6.91 (s, 1H), 6.70
25 (br s, 2H), 6.04 (s, 2H), 4.88 (s, 2H), 3.53 (q, J= 7.0 Hz, 2H), 1.02 (t, /= 7.0 Hz, 3H);
HRMS (ESI) calcd for C 23 H2iN 5 0 2 : 400.1774; found: 400.1784.
Examples 38 -65
Part A
30 The methods described in Examples 30 and 3 1 were repeated on a larger scale to
provide (4-amino-l-{[3-(4-fluorophenyl)isoxazol-5-yl]^^
c]quinolin-2-yl)methanol. The reaction described in Example 31 was heated at reflux and
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was complete within three hours. Thionyl chloride (0.45 mL, 6.17 mmol) was added
dropwise to a suspension of (4-ainino-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l J ff-
imidazo[4,5-c]quinolin-2-yl)methanol (1.2 g, 3.08 mmol) in dichloromethane (30 mL),
and the mixture was stirred at room temperature for 1.8 hours. The volatiles were
removed under reduced pressure, and the residue was combined with material from
another run, triturated with a mixture of ethanol and diethyl ether, and isolated by filtration
to provide 1.54 g 2-(chloromethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-l/f-
imidazo[4,5-c]quinolin-4-amine hydrochloride.
PartB
A secondary amine (0.15 mmol, 1.5 equivalents) from the table below was added
to a test tube containing 2-(chloromethyl)-l-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-
1 //-imidazo [4,5 -c] quinolin-4- amine hydrochloride (44 mg, 0.097 mmol), N,N-
diisopropylethylamine (0.057 mL, 0.33 mmol), and A^dimethylacetamide (DMA) (1
mL). The test tube was capped and heated overnight at 60 °C. The volatiles were
removed from each tube by vacuum centrifugation.
The compounds were purified by reversed phase prep HPLC using a Waters
FractionLynx automated purification system. The prep HPLC fractions were analyzed
using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to
provide the trifluoroacetate salt of the desired compound. Reversed phase preparative
liquid chromatography was performed with non-linear gradient elution from 5-95% B
where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic
acid/acetonitrile. Fractions were collected by mass-selective triggering. The table below
shows the reagent added to each test tube, the structure of the resulting compound, and the
observed accurate mass for the isolated trifluoroacetate salt.
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Examples 38-65
NH 2
*" F
Example
Reagent
R
Measured
Mass (M+H)
38
None
CI
/
408.1008
39
Pyrrolidine
0
/
443.1994
40
2-(Methylamino)ethanol
h 3 c r OH
N —
/
447.1921
41
Piperidine
/ V
o
457.2122
42
Morpholine
/
459.1958
43
//-Ethyl-N-propylamine
H 3 C-^ /-CH 3
459.2310
44
2-Ethylaminoethanol
H 3 C-\ ^-OH
N —
/
461.2097
45
3-Methylpiperidine
471.2268
46
4-Methylpiperidine
CHL
o
r
471.2292
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47
1 -Methylpiperazine
CH 3
/
472.2256
48
3 -Hvdroxvoio eridine
( VoH
N— '
/
473.2093
49
4-Hydroxypiperidine
OH
r\
V>
/
473.2111
50
2-(Propylamino)ethanol
H,C
^— \ /-OH
N —
/
475.2244
51
Diethanolamine
HO
V — \ r OH
N — '
/
477.2047
52
iV-Methylaniline
H 3 Q /~\
479.2035
53
3-
(Cyclopropylamino)propionitrile
482.2105
N-
Propylcyclopropanemethylamine
h 3 c r>
\l — '
/
485 2430
55
3-(Dimethylamino)pyrrolidine
CH 3
N
/
486.2397
iv-Meinyuioniopiperazine
/
57
2-Piperidinemethanol
ft
' ^-OH
487.2227
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CO
Do
d -\jtiy ui uxymcLnyi jpipenuine
C\w 0H
N —
/
4o/.ZZ80
59
4-(Hydroxymethyl)piperidine
^OH
o
N — '
/
487.2223
60
N-Methylbenzylamine
0
/
493.2114
OI
Isonipecotamide
H.N
O
/
500.2188
62
Nipecotamide
NH 2
500.2159
63
l-Methyl-4-
(Methylamino)piperidine
N— ( N-CH-
500.2526
OH
Isonipecotic acid
HO
O
/
65
Nipecotic acid
/
501.2013
Exemplary Compounds
Certain exemplary compounds, including some of those described above in the
5 Examples, have the following Formulas (lib, He, Hie, md, IVc, IVd, Vc, or Vd) and the
following R' and R2 substituents, wherein each line of the table is matched with Formula
lib, lie, Hie, Hid, IVc, IVd, Vc, or Vd to represent a specific embodiment of the invention.
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Vc Vd
R'
R 2
methyl
hydrogen
phenyl
hydrogen
4-fluorophenyl
hydrogen
pyridin-3~yl
hydrogen
methyl
methyl
phenyl
methyl
4-fluorophenyl
methyl
pyridin-3-yl
methyl
methyl
ethyl
phenyl
ethyl
4-fluorophenyl
ethyl
pyridin-3-yl
ethyl
methyl
n-propyl
phenyl
n-propyl
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4-fluorophenyl
n-propyl
pyridin-3-yl
n-propyl
methyl
ethoxymethyl
phenyl
ethoxymethyl
4-fluorophenyl
ethoxymethyl
pyridin-3-yl
ethoxymethyl
methyl
hydroxymethyl
phenyl
hydroxymethyl
4-fluorophenyl
hydroxymethyl
pyridin-3-yl
hydroxymethyl
methyl
2-hydroxyethyl
phenyl
2-hydroxyethyl
4-fluorophenyl
2-hydroxyethyl
pyridin-3-yl
2-hydroxyethyl
methyl
fluoromethyl
phenyl
fluoromethyl
4-fluorophenyl
fluoromethyl
pyridin-3-yl
fluoromethyl
Certain exemplary compounds, including some of those described above in the
Examples, have the following Formulas (lid, Hie, IVe,or Ve) and the following R 1 and R 2
substituents, wherein each line of the table is matched with Formula Ed, Hie, IVe 5 or Ve to
5 represent a specific embodiment of the invention.
Hd Kte
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IVe
R
R2
butyl
hydrogen
phenyl
hydrogen
4-fluorophenyl
hydrogen
pyndin-3-yl
hydrogen
butyl
methyl
phenyl
methyl
4-fluorophenyl
methyl
pyndin-3-yl
methyl
butyl
ethyl .
phenyl
ethyl
4-fluorophenyl
ethyl
pyridin-3-yl
< i 1
ethyl
butyl
n-propyl
n-propyj
4-fluorophenyl
n-propyl
pyridin-3-yl
n-propyl
butyl
ethoxymethyl
phenyl
ethoxymethyl
4-fluorophenyl
ethoxymethyl
pyridin-3-yl
ethoxymethyl
butyl
hydroxymethyl
phenyl
hydroxymethyl
4-fluorophenyl
hydroxymethyl
pyridin-3-yl
hydroxymethyl
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butyl
2-hydroxyetbyl
phenyl
2-hydroxyethyl
4-fluorophenyl
2-hydroxyethyl
pyridin-3-yl
2-hydroxyethyl
butyl
fluoromethyl
phenyl
fluoromethyl
4-fluorophenyl
fluoromethyl
pyridin-3-yl
fluoromethyl
Compounds of the invention have been found to induce cytokine biosynthesis
when tested using the methods described below.
5
CYTOKINE INDUCTION IN HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction. Activity
is based on the measurement of interferon (a) and tumor necrosis factor (a) (IFN-a and
TNF-a, respectively) secreted into culture media as described by Testerman et. al. in
10 "Cytokine Induction by the Immunomodulators Imiquimod and S-27609" Journal of
Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into
15 vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells
(PBMC) are separated from whole blood by density gradient centrifiigation using
HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham
Biosciences Piscataway, NJ). Blood is diluted 1:1 with Dulbecco's Phosphate Buffered
Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). Alternately, whole blood is
20 placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL)
centrifuge frit tubes containing density gradient medium. The PBMC layer is collected
and washed twice with DPBS or HBSS and re-suspended at 4 x 10 6 cells/mL in RPMI
complete. The PBMC suspension is added to 96 well flat bottom sterile tissue culture
plates containing an equal volume of RPMI complete media containing test compound.
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Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO
concentration should not exceed a final concentration of 1% for addition to the culture
5 wells. The compounds are generally tested at concentrations ranging from 30-0.014 |xM.
Controls include cell samples with media only, cell samples with DMSO only (no
compound), and cell samples with reference compound.
Incubation
10 The solution of test compound is added at 60 \xM to the first well containing RPMI
complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then
added to the wells in an equal volume, bringing the test compound concentrations to the
desired range (usually 30-0.014 \iM). The final concentration of PBMC suspension is 2 x
10 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then
15 incubated for 1 8 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Separation
Following incubation the plates are centrifiiged for 10 minutes at 1000 rpm
(approximately 200 x g) at 4°C. The cell-free culture supernatant is removed and
20 transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until
analysis. The samples are analyzed for IFN-a by ELIS A and for TNF-a by
IGEN/BioVeris Assay.
Interferon (a) and Tumor Necrosis Factor (a) Analysis
25 IFN-a concentration is determined with a human multi-subtype colorimetric
sandwich ELIS A (Catalog Number 41 105) from PBL Biomedical Laboratories,
Piscataway, NJ. Results are expressed in pg/mL.
The TNF-a concentration is determined by ORIGEN M-Series Immunoassay and
read on an IGEN M-8 analyzer from BioVeris Corporation, formerly known as IGEN
30 International, Gaithersburg, MD. The immunoassay uses a human TNF-a capture and
detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource
International, Camarillo, CA. Results are expressed in pg/mL.
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Assay Data and Analysis
In total, the data output of the assay consists of concentration values of TNF-a and
IFN-a (y-axis) as a function of compound concentration (x-axis).
5 Analysis of the data has two steps. First, the greater of the mean DMSO (DMSO
control wells) or the experimental background (usually 20 pg/mL for IFN-a and 40 pg/mL
for TNF-a) is subtracted from each reading. If any negative values result from
background subtraction, the reading is reported as " * and is noted as not reliably
detectable. In subsequent calculations and statistics, " * ", is treated as a zero. Second, all
10 background subtracted values are multiplied by a single adjustment ratio to decrease
experiment to experiment variability. The adjustment ratio is the area of the reference
compound in the new experiment divided by the expected area of the reference compound
based on the past 61 experiments (unadjusted readings). This results in the scaling of the
reading (y-axis) for the new data without changing the shape of the dose-response curve.
1 5 The reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a-
dimethyl-li/-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5.352,784;
Example 91) and the expected area is the sum of the median dose values from the past 61
experiments.
The minimum effective concentration is calculated based on the background-
20 subtracted, reference-adjusted results for a given experiment and compound. The
minimum effective concentration (jimolar) is the lowest of the tested compound
concentrations that induces a response over a fixed cytokine concentration for the tested
cytokine (usually 20 pg/mL for IFN-a and 40 pg/mL for TNF-a). The maximal response
is the maximal amount of cytokine (pg/ml) produced in the dose-response.
25
CYTOKINE INDUCTION IN HUMAN CELLS
(High Throughput Screen)
The CYTOKINE INDUCTION IN HUMAN CELLS test method described above
was modified as follows for high throughput screening.
30
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Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into
vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells
(PBMC) are separated from whole blood by density gradient centrifugation using
HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham
Biosciences Piscataway, NJ). Whole blood is placed in Accuspin (Sigma) or LeucoSep
(Greiner Bio-One, Inc., Longwood, FL) centrifuge frit tubes containing density gradient
medium. The PBMC layer is collected and washed twice with DPBS or HBSS and re-
suspended at 4 x 10 6 cells/mL in RPMI complete (2-fold the final cell density). The PBMC
suspension is added to 96- well flat bottom sterile tissue culture plates.
Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The compounds
are generally tested at concentrations ranging from 30 - 0.014 |iM. Controls include cell
samples with media only, cell samples with DMSO only (no compound), and cell samples
with a reference compound 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a-dimethyl-
lH-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91)
on each plate. The solution of test compound is added at 7.5 mM to the first well of a
dosing plate and serial 3 fold dilutions are made for the 7 subsequent concentrations in
DMSO. RPMI Complete media is then added to the test compound dilutions in order to
reach a final compound concentration of 2-fold higher (60 - 0.028 jiM) than the final
tested concentration range.
Incubation
Compound solution is then added to the wells containing the PBMC suspension
bringing the test compound concentrations to the desired range (usually 30 - 0.014 |iM)
and the DMSO concentration to 0.4 %. The final concentration of PBMC suspension is
2xl0 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then
incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Separation
Following incubation the plates are centrifuged for 10 minutes at 1000 rpm
(approximately 200 g) at 4°C. 4-plex Human Panel MSD MULTI-SPOT 96-well plates
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are pre-coated with the appropriate capture antibodies by MesoScale Discovery, Inc.
(MSD, Gaithersburg, MD). The cell-free culture supematants are removed and transferred
to the MSD plates. Fresh samples are typically tested, although they may be maintained at
-30 to -70°C until analysis.
5
Interferon-a and Tumor Necrosis Factor-a Analysis
MSD MULTI-SPOT plates contain within each well capture antibodies for human
TNF-a and human IFN-a that have been pre-coated on specific spots. Each well contains
four spots: one human TNF-a capture antibody (MSD) spot, one human IFN- a capture
10 antibody (PBL Biomedical Laboratories, Piscataway, NJ) spot, and two inactive bovine
serum albumin spots. The human TNF-a capture and detection antibody pair is from
MesoScale Discovery. The human IFN-a multi-subtype antibody (PBL Biomedical
Laboratories) captures all IFN-a subtypes except IFN-a F (IFNA21). Standards consist of
recombinant human TNF-a (R&D Systems, Minneapolis, MN) and IFN-a (PBL
15 Biomedical Laboratories). Samples and separate standards are added at the time of
analysis to each MSD plate. Two human IFN-a detection antibodies (Cat. Nos. 21 1 12 &
21 100, PBL) are used in a two to one ratio (weight :weight) to each other to determine the
IFN-a concentrations. The cytokine-specific detection antibodies are labeled with the
SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeled detection antibodies
20 to the wells, each well's electrochemoluminescent levels are read using MSD's SECTOR
HTS READER. Results are expressed in pg/mL upon calculation with known cytokine
standards.
Assay Data and Analysis
25 In total, the data output of the assay consists of concentration values of TNF-a or
IFN-a (y-axis) as a function of compound concentration (x-axis).
A plate-wise scaling is performed within a given experiment aimed at reducing
plate-to-plate variability associated within the same experiment. First, the greater of the
median DMSO (DMSO control wells) or the experimental background (usually 20 pg/mL
30 for IFN-a and 40 pg/mL for TNF-a) is subtracted from each reading. Negative values that
may result from background subtraction are set to zero. Each plate within a given
experiment has a reference compound that serves as a control. This control is used to
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calculate a median expected area under the curve across all plates in the assay. A plate-
wise scaling factor is calculated for each plate as a ratio of the area of the reference
compound on the particular plate to the median expected area for the entire experiment.
The data from each plate are then multiplied by the plate-wise scaling factor for all plates.
5 Only data from plates bearing a scaling factor of between 0.5 and 2.0 (for both cytokines
IFN-a, TNF-a) are reported. Data from plates with scaling factors outside the above
mentioned interval are retested until they bear scaling factors inside the above mentioned
interval. The above method produces a scaling of the y-values without altering the shape
of the curve. The reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-
10 tetrahydro-a 3 a-dimethyl-li7-imidazo[4 3 5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No.
5,352,784; Example 91). The median expected area is the median area across all plates
that are part of a given experiment.
A second scaling may also be performed to reduce inter-experiment variability
(across multiple experiments). All background-subtracted values are multiplied by a
15 single adjustment ratio to decrease experiment-to-experiment variability. The adjustment
ratio is the area of the reference compound in the new experiment divided by the expected
area of the reference compound based on an average of previous experiments (unadjusted
readings). This results in the scaling of the reading (y-axis) for the new data without
changing the shape of the dose-response curve. The reference compound used is 2-[4-
20 amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a^
yljethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the
sum of the median dose values from an average of previous experiments.
The minimum effective concentration is calculated based on the background-
subtracted, reference-adjusted results for a given experiment and compound. The
25 minimum effective concentration (jimolar) is the lowest of the tested compound
concentrations that induces a response over a fixed cytokine concentration for the tested
cytokine (usually 20 pg/mL for IFN-a and 40 pg/mL for TNF-a). The maximal response
is the maximal amount of cytokine (pg/ml) produced in the dose-response.
30
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The complete disclosures of the patents, patent documents, and publications cited
herein are incorporated by reference in their entirety as if each were individually
incorporated. Various modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the scope and spirit of this
invention. It should be understood that this invention is not intended to be unduly limited
by the illustrative embodiments and examples set forth herein and that such examples and
embodiments are presented by way of example only with the scope of the invention
intended to be limited only by the claims set forth herein as follows.
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10
WHAT IS CLAIMED IS:
1 . A compound of the Formula I:
NH 2
I
R B T \
R A X'-R,
I
wherein:
X' is selected from the group consisting of -CH(R 9 >, -CH(R.9)-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
~A n ^ n -4* -^ R ', i> Jr
R' R' N'° N' U R R' O-N
> > > > » »
R'
_^/~0^- Ri2 R -C(R 9a ) 2 -N-N
R' Rn. A 1 R c R-
R'
C(Rg a ) 2 — N^"N
K 12
K A. V y
, and
R' is selected from the group consisting of:
hydrogen,
15 alkyl,
alkenyl,
aryl,
arylalkylenyl,
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heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(O) 0 -2-alkyl,
-S(0)o_ 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
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Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(Rp)2; or Rc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
5 Ri i is Ci-6 alkylene or C 2 -6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, Cm alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
1 0 wherein the total number of atoms in the ring which includes Ri 1 or R12 is 4 to 9;
A' is selected from the group consisting of -O-, -S(0)o-2-> -NO-Q-R4)-, and
-C(R9a)2S
R A and Rb are each independently selected from the group consisting of:
hydrogen,
15 halogen,
alkyl,
alkenyl,
alkoxy,
alkylthio, and
20 -N(R 9 ) 2 ;
or R A and R B taken together form either a fused aryl ring that is unsubstituted or
substituted by one or more R* groups, or a fused 5 to 7 membered saturated ring that is
unsubstituted or substituted by one or more R^ groups;
or R A and R B taken together form a fused heteroaryl or 5 to 7 membered saturated
25 ring containing one heteroatom selected from the group consisting of N and S, wherein the
heteroaryl ring is unsubstituted or substituted by one or more R b groups, and the 5 to 7
membered saturated ring is unsubstituted or substituted by one or more R e groups;
Ra is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
30 Rb is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl,
alkoxy, and -N(R9>2;
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R« is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
R 2 is selected from the group consisting of:
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0)2-N(R8)- ;
-C(R«)-,
-C(R 6 )-0-,
-0-C(R<5)-,
-0-C(0)-0-
-N(R 8 )-Q-,
-C(R6)-N(R8)-,
-0-C(R6)-N(R8)-,
-C(R6)-N(OR 9 )-,
J- N-Q —
Rt is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
, and
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heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(O) 0 -2-, -CH 2 -> and
-N(R4>;
Q is selected from the group consisting of a bond, -C(R<s)-, -C(R6)-C(R6)-> -S(0)2-,
and-S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R^)-, -0-C(R^)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
, and
<7;
or a pharmaceutical^ acceptable salt thereof.
2.
A compound of the Formula II:
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wherein:
X f is selected from the group consisting of -CH(R9)-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
°j: ^ • _^ ri "ft*
9 3 > 5 9 9
R'
i l^-R^ I* 1 1 -C(R 9a ) 2 -N^N R
, \ * R,i^ - R11
R' R 11 A- R c R R' V-
, and
R'
-C(R 9a ) 2 -N^N
O
R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
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alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)ou 2 -alkyl,
-S(0)o- 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and-N(R 9 ) 2 ; orRc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
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Ri i is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
5 heteroatom;
wherein the total number of atoms in the ring which includes Rn or R12 is 4 to 9;
A' is selected from the group consisting of -0-, -S(0)o-2-, -N(-Q-R4)-, and
-C(R 9 a) 2 S
Rai and Rbi are each independently selected from the group consisting of:
10 hydrogen,
halogen,
alkyl,
alkenyl,
alkoxy,
15 alkylthio, and
-N(R 9 ) 2 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
20 -X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
25 heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(Rs)-,
-C(R6>,
30 -C(R6)-0-,
-0-C(R6>,
-0-C(0)-Ch
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-N(R«)-Q-,
-C(R«)-N(R,)-,
-0-C(R6)-N(R8)-,
-C(R6)-N(OR 9 )-,
N-Q —
R ^
K 10
— N— R 7 -N-Q-
* 7 ,and
-V-N
10
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
-N-C(R 6 ) -N-S(0) 2 _ v _,4 2 M
R ? , * 7 ,and \cH 2 ) b -^.
Re is selected from the group consisting of =0 and =S;
R 7 is C2.7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and C M alkyl;
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Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -8(0)0-2-, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(0) 2 -,
and.S(0) 2 -N(R8)-;
V is selected from the group consisting of -C(R 6 )-, -0-C(R6)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
X' is selected from the group consisting of -CHfR^)-, -CH(R-9)-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
<7;
or a pharmaceutical^ acceptable salt thereof.
3.
A compound of the Formula III:
NH.
wherein:
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R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
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-S(0)o- 2 -alkyl,
-S(0)o-2-aryl 9
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-O-alkyl,
-C(0)-N(EU) 2 ,
>N(R8)-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R4 are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and-N(R 9 ) 2 ; or Rc and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is C1-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1.5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes R } 1 or R l2 is 4 to 9;
A 1 is selected from the group consisting of -O, -S(O) 0 - 2 -, -N(-Q-R4>, and
-C(R 9a ) 2 -;
Ra is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
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n is an integer from 0 to 4;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-C(R6)-,
-C(R6)-0-,
-0-C(R6)-,
-0-C(0)-0-,
-N(R8)-Q-,
-C(R6)-N(R 8 >,
-0-C(R6)-N(Rg)-,
-C(R6)-N(OR 9 )-,
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
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alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
5 hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo ;
R 5 is selected from the group consisting of:
-N-C(Re) -N~S(0) 2 _ v _rf ^
10 W , R / ,and Wr^.
R<s is selected from the group consisting of =0 and =S;
R 7 is C 2 -7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
15 R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o- 2 -, -CH 2 -, and
-N(R4)-;
20 Q is selected from the group consisting of a bond, -C(R6)-, -C(R6>C(R<s)-, -S(0) 2 -,
and -S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R$)-, -OC(R<s)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
25 or a pharmaceutical^ acceptable salt thereof.
4. A compound of the Formula IV:
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IV
wherein:
X' is selected from the group consisting of -CH(R 9 >, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
> i> J r
R' R" NT W N" U R' R' O-N
> J > » 9 ?
FT
J
R'
Rii ^
, and
9
R is selected from the group consisting of:
10 hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
15 heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
20 heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
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alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)o- 2 -alkyl,
-S(O) 0 . 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0>N(R8) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or Rc and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, Ci_ 5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
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wherein the total number of atoms in the ring which includes Rn or R12 is 4 to 9;
A' is selected from the group consisting of -0-, -S(0)o-2-, -N(-Q-R0-, and
Re is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloaUcyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
n is an integer of 0 to 4;
R2 is selected from the group consisting of:
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(Rs)-,
-C(R6>,
-C(R6>0-,
-0-C(Rs)-,
-0-C(0)-0-
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-O-C^-NCRs)-,
-C(R6)-N(OR 9 )-,
-C N-Q —
-C(R 9a )2-;
-R4,
-X-R,,
-X-Y-R,, and
-X-R 5 ;
, and
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— V-N
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
Rs is selected from the group consisting of:
R$ is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C 3 _8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 - 2 -, -CH 2 -, and
Q is selected from the group consisting of a bond, -C(R<5)-, -C(R«)-C(R6)-, -S(0) 2 -,
and -S(0) 2 -N(R8)-;
V is selected from the group consisting of -COEU)-, -0-C(R6)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
or a pharmaceutical^ acceptable salt thereof.
— N — C(Re) — N— S(0) 2
, and
—V-N
/-(CH 2 ) a x
N A
\ A
-N(R4>;
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5. A compound selected from the group consisting of the Formulas V, VI, VII, and
vm:
V VI
wherein:
X ! is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene~;
Ri is selected from the group consisting of:
R' is selected from the group consisting of:
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hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(0)o- 2 -alkyl,
-S(0)o- 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0~alkyl,
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-C(0)-N(Rs) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9> 2 ; or Rc and
Ra can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Ri i is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C\.s alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or Ri 2 is 4 to 9;
A 1 is selected from the group consisting of -0-, -S(O) 0 -2-, -N(-Q-R4)-, and
-C(R 9a )2-;
Rb is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl,
alkoxy, and -N(R9> 2 ;
m is an integer from 0 to 3;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 K
-C(R<0-,
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-C(R6)-0-,
-0-C(R6H
-0-C(0)-0-.
-N(R 8 )-Q-,
5
-C(R«)-N(R«K
-0-C(R6)-N(R 8 )-,
-C(R6)-N(OR9h
10
and
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
15 heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
20 (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
25
R$ is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
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Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rg a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(0>, -S(O) 0 . 2 -, -CH 2 -, and
-NCR4)-;
Q is selected from the group consisting of a bond, -C(R<0-, -C(R*)-C(R6)-, -S(0) 2 -,
and-S(0) 2 -N(R 8 >;
V is selected from the group consisting of -C(R<>)-, -0-C(R6>, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
or a pharmaceutical^ acceptable salt thereof.
6. A compound selected from the group consisting the Formulas IXa, DCb, IXc, and
IXd:
, and
wherein:
X 1 is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
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R f is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
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-S(0)o-2-alkyl,
-S(0)o-2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyi;
Rc and R<j are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or Rc and
R<i can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenyl ene is
optionally interrupted by one heteroatom;
Ri 2 is selected from the group consisting of a bond, C1-5 alkylene, and
C 2 _5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or Ri 2 is 4 to 9;
A 1 is selected from the group consisting of -O-, -S(0)o- 2 -, -N(-Q-R4)-, and
-C(R 9a )2-;
Re is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R 9 )2;
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m is an integer from 0 to 3;
R.2 is selected from the group consisting of:
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-C(R*)-0-,
-0-C(0)-0-,
-N(Rs)-Q-,
-C(R«>N(R«)-,
-0-C(R 6 )-N(R 8 )-,
-C(R«)-N(OR 9 )-,
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
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alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylatnino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
R6 is selected from the group consisting of =0 and =S;
R 7 is C2.7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -O, -C(O)-, -S(0)o-2-, -CH2-, and
-NCR,)-;
Q is selected from the group consisting of a bond, -C(R6)- 5 -C(R$)-C(R6)-, -S(0)2-,
and-S(0) 2 -N(R 8 )s
V is selected from the group consisting of -C(R6>, ~OC(R6)-, and -S(0)2-; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
, and
<7;
or a pharmaceutically acceptable salt thereof.
7.
A compound of the Formula 1-1 :
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Ra
I-l
wherein:
G is selected from the group consisting of:
5 -C(0)-R",
a-aminoacyl,
a-aminoacyl-a-aminoacyl,
-C(0)-0-R M ,
-C(0)-N(R m )R",
10 -C(=NY')-R",
-CH(OH)-C(0)-OY\
-CH(OC M alkyl)Y 0 ,
-CH 2 Yi, and
-CH(CH 3 )Y i;
1 5 R" and R m are independently selected from the group consisting of C M o alkyl,
C3-7 cycloalkyl, and benzyl, each of which may be unsubstituted or substituted by one or
more substitutents selected from the group consisting of halogen, hydroxy, nitro, cyano,
carboxy, alkyl, Ci^alkoxy, aryl, heteroaryl, arylCi-4 alkylenyl,
heteroarylC M alkylenyl, haloCi-4 alkylenyl, haloC M alkoxy, ~0-C(0)-CH 3 , -C(0)-0-CH 3 ,
20 -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso that R" ? can also
be hydrogen;
a-aminoacyl is an acyl group derived from an amino acid selected from the group
consisting of racemic, D-, and L-amino acids;
Y* is selected from the group consisting of hydrogen, alkyl, and benzyl;
25 Y 0 is selected from the group consisting of C1-6 alkyl, carboxyCi-6 alkylenyl,
aminoCi-4 alkylenyl, mono-N-Ci. 6 alkylaminoCi-4 alkylenyl, and
di-N,N-C\^ alkylaminoCi-4 alkylenyl;
Yi is selected from the group consisting of mono-MCi-6 alkylamino,
di-N,N-C\4 alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and
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4-Ci-4 alkylpiperazin-l-yl;
X* is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
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haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(O) 0 . 2 -alkyl,
-S(0)o-2-aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
Rc and R<i are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or Rc and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci-6 alkylene or C 2 -6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R J2 is selected from the group consisting of a bond, d- 5 alkylene, and
C 2 . 5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes Rn or Ri 2 is 4 to 9;
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A 1 is selected from the group consisting of -0-, -S(O) 0 -2~, -N(-Q-R4>, and
-C(R 9a ) 2 -;
Ra and R B are each independently selected from the group consisting of:
hydrogen,
5 halogen,
alkyl,
alkenyl,
alkoxy,
alkylthio, and
10 -N(R 9 ) 2 ;
or R A and R B taken together form either a fused aryl ring that is unsubstituted or
substituted by one or more R a groups, or a fused 5 to 7 membered saturated ring that is
unsubstituted or substituted by one or more Re groups;
or R A and R B taken together form a fused heteroaryl or 5 to 7 membered saturated
15 ring containing one heteroatom selected from the group consisting of N and S, wherein the
heteroaryl ring is unsubstituted or substituted by one or more R b groups, and the 5 to 7
membered saturated ring is unsubstituted or substituted by one or more Re groups;
Ra is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
20 Rb is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl,
alkoxy, and -N(R 9 ) 2 ;
Re is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl,
haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
R 2 is selected from the group consisting of:
25 -R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
30 arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
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Y is selected from the group consisting of:
-S(0)o. 2 -,
-S(0) 2 -N(R 8 )-,
-C(R6h
-C(R6)-0-,
-O-CCR*)-,
-0-C(0)-0-,
-N(R8>Q-,
-C(R6)-N(R8)-,
-0-C(R6)-N(R 8 K
-C(R*>N(OR 9 )-,
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
, and
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-N-C(R 6 ) -N-S(0) 2 _ v _^j A
Cr 7^ , R ^ ,and W
R<s is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -C(O)-, -S(0)o-2-, -CH 2 -, and
-N(R4)s
Q is selected from the group consisting of a bond, -C(R6)-, -C(R 6 )-C(R6)-, -S(0) 2 -,
and -S(0) 2 -N(R 8 )S
V is selected from the group consisting of -C(R6)-, -0-C(R6)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
or a pharmaceutical^ acceptable salt thereof
8. The compound or salt of claim 2 wherein R A i and R B i are each methyl.
9. The compound or salt of claim 3 or claim 4 wherein n is 0.
10. The compound or salt of claim 5 wherein the compound is Formula V:
NhL
V
or a pharmaceutical^ acceptable salt thereof.
1 1 . The compound or salt of claim 6 wherein the compound is Formulas DCa:
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or a pharmaceutically acceptable salt thereof.
■
5 12. The compound or salt of any one of claims 5, 6, 1 0, and 1 1 wherein m is 0.
1 3 . The compound or salt of any one of claims 1 through 1 2 wherein X' is
Cm alkylene.
10 14. The compound or salt of claim 1 3 wherein X 1 is -CH2-.
15. The compound or salt of any one of claims 1 through 14 wherein Ri is selected
from the group consisting of:
15
d ; and Rg is selected from the group consisting of hydrogen, alkyl,
alkoxyalkylenyl, and arylalkylenyl.
16. The compound or salt of any one of claims 1 through 14 wherein:
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Ri is selected from the group consisting of:
R'
each R a is independently selected from the group consisting of fluorine, alkyl,
haloalkyl, alkoxy, and -N(R 9 ) 2 ; and
each Rg is independently selected from the group consisting of hydrogen, alkyl,
alkoxyalkylenyl, and arylalkylenyl.
17. The compound or salt of any one of claims 1 through 14 wherein R\ is selected
from the group consisting of:
19. The compound or salt of any one of claims 1 through 14 wherein Ri is selected
from the group consisting of:
R ' and
18. The compound or salt of claim 17 wherein Ri is
R'
C(RJ2-N^N
R 1
, and
20. The compound or salt of claim 19 wherein R\ is
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21 . The compound or salt of any one of claims 1 through 14 wherein Ri is
5
22. The compound or salt of any one of claims 1 through 21 wherein R r is selected
from the group consisting of alkyl, aryl, and heteroaryl, each of which is unsubstituted or
substituted by one or more substituents selected from the group consisting of alkyl,
alkoxy, halogen, and haloalkyl.
10
23. The compound or salt of claim 22 wherein R ! is selected from the group consisting
of methyl; butyl; phenyl which is unsubstituted or substituted by one or more substituents
selected from the group consisting of fluorine and trifluoromethyl; and 3-pyridyl.
15 24. The compound or salt of any one of claims 1 through 23 wherein R 2 is hydrogen;
alkoxyalkylenyl; hydroxyalkylenyl; haloalkylenyl;.heterocyclylalkylenyl that is
unsubstituted or substituted by one or more substituents selected from the group consisting
of methyl, hydroxy, hydroxymethyl, and dimethylamino; -R4; -X-R4; or -X-Y-R4; wherein:
X is Ct-2 alkylene optionally terminated by heterocyclylene;
20 Y is -S(O) 0 -2-, -S(0)rN(R8)-, -COfch -C^-O-, -O-CCR*)-, -O-C(O)-0-,
-N(Rs)-Q-, -C(R6)-N(Rs)-, -0-C(R«)-N(Rs)-, or -C(R 6 )-N(OR 9 )s wherein
R 8 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl,
and hydroxyalkylenyl; and
R4 is alkyl that is unsubstituted or substituted by one or more substituents selected
25 from the group consisting of hydroxy and cyano, aryl; or heterocyclyl that is unsubstituted
or substituted by alkyl with the proviso that when Y is -C(Rs)-0- or -C(R6)-N(R8)-, then
R4 may also be hydrogen.
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25. The compound or salt of claim 24 wherein R 2 is hydrogen, alkoxyalkylenyl,
hydroxyalkylenyl, -R4, -X-R4, or -X-Y-R4; wherein:
X is C1.2 alkylene;
Y is -S(0)o. 2 -, -S(0) 2 -N(R 8 )-, -C(R«K -C(R 6 )-0-, -O-CORo)-, -0-C(0)-0-,
-N(R«>Q-, -C(R6)-N(R8)-, -0-C(R6)-N(R 8 )- ? or -C(R6)-N(OR 9 )-; wherein
Rg is selected from the group consisting of hydrogen, alkyl, and
arylalkylenyl; and
R4 is alkyl.
26. The compound or salt of claim 25 wherein R 2 is hydrogen, Cm alkyl,
Cm alkyl-O-CM alkylenyl, or hydroxyC^ alkylenyl.
27. The compound or salt of claim 26 wherein R 2 is methyl, ethyl, w-propyl, /z-butyl,
ethoxymethyl, 2-methoxyethyl, hydroxymethyl, or 2-hydroxyethyl.
28. The compound or salt of claim 24 wherein R 2 is methyl, ethyl, 72-propyl, «-butyl,
ethoxymethyl, 2-methoxyethyl, hydroxymethyl, 2-hydroxyethyl, or fluoromethyl.
29. A pharmaceutical composition comprising a therapeutically effective amount of a
compound or salt of any one of claims 1 through 28 and a pharmaceutical^ acceptable
carrier.
30. A method of inducing cytokine biosynthesis in an animal comprising administering
an effective amount of a compound or salt of any one claims 1 through 28 or the
pharmaceutical composition of claim 29 to the animal.
31. A method of treating a viral disease in an animal in need thereof comprising
administering a therapeutically effective amount of a compound or salt of any one of
claims 1 through 28 or the pharmaceutical composition of claim 29 to the animal.
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32. A method of treating a neoplastic disease in an animal in need thereof comprising
administering a therapeutically effective amount of a compound or salt of any one of
claims 1 through 28 or the pharmaceutical composition of claim 29 to the animal.
5 33 . A compound of the Formula X:
CI
wherein:
10
X' is selected from the group consisting of -CH(R 9 )-, -CH(R 9 )-alkylene-, and
-CH(R 9 )-alkenylene-;
Ri is selected from the group consisting of:
—i
R' R„ A'
C(R9 a ) 2 -N N
A 6
, and
15
R' is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
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arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl,
heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected
from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
-S(O) 0 .2-alkyl,
-S(0)o. 2 -aryl,
-NH-S(0) 2 -alkyl,
-NH-S(0) 2 -aryl,
haloalkoxy,
halogen,
nitrile,
nitro,
aryl,
heteroaryl,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
-C(0)-0-alkyl,
-C(0)-N(R 8 ) 2 ,
-N(R 8 )-C(0)-alkyl,
-0-(CO)-alkyl, and
-C(0)-alkyl;
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Rc and are independently selected from the group consisting of hydrogen,
halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and-N(R 9 ) 2 ; orRc and
R<j can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing
one to four heteroatoms;
Rn is Ci_6 alkylene or C 2 _ 6 alkenylene, wherein the alkylene or alkenylene is
optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C N5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one
heteroatom;
wherein the total number of atoms in the ring which includes R x } or R n is 4 to 9;
A' is selected from the group consisting of -O, -S(O) 0 - 2 -, -N(-Q-R4)-, and
-C(R9a) 2 S
Ra is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and
-N(R 9 ) 2 ;
n is an integer from 0 to 4;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X~R 5 ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups are optionally interrupted or terminated by arylene, heteroarylene or
heterocyclylene and optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(0)o_ 2 -,
-S(0) 2 -N(R 8 )-,
-C(R 6 )-,
-C(R6)-0-,
-0-C(R6)-,
-0-C(0)-CK
-NCRs)-Q-,
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-C(R6)-N(R8>,
-O-C^-NCRs)-,
-C^-NCORs)-,
N-Q—
K 10
-N— R 7 -N-Q-
*V s and
— V-N
9
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
are unsubstituted or substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
-N-C(R 6 ) -N-S(0) 2 ^. v _j(f (CH2)a ^
V , R ^ .and
Rs is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, and arylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 9a is selected from the group consisting of hydrogen and Cm alkyl;
Rio is C3-8 alkylene;
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A is selected from the group consisting of -0-, -C(O)-, -S(O) 0 - 2 -, -CH 2 -, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(R«)-, -C^-C^)-, -S(0) 2 -,
and -S(0) 2 -N(R 8 )-;
V is selected from the group consisting of -C(R<;)-, -0-C(R<;)-, and -S(0) 2 -; and
a and b are each independently an integer from 1 to 6 with the proviso that a + b is
<7;
or a phaimaceuticaliy acceptable salt thereof.
198
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